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Antibodies in Cancer Treatment

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 33154

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Dr. Anthony Cheung

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Guest Editor

1. St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London, Guy’s Hospital, London SE1 9RT, UK
2. Breast Cancer Now Research Unit, King’s College London, Guy’s Cancer Centre, London SE1 9RT, UK
Interests: triple negative breast cancer; antibody-drug conjugate; antibody targeted therapy; biomarker discovery; tumor microenvironment
Special Issues, Collections and Topics in MDPI journals

Dr. Heather Bax

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Guest Editor

St. John's Institute of Dermatology, King's College London & NIHR Biomedical Research Centre at Guy's and St. Thomas's Hospitals and King's College London, London SE1 9RT, UK
Interests: IgE antibodies against cancer; tumor microenvironment; mechanistic and safety studies; early clinical trials; basophils; macrophages/monocytes

Special Issue Information

Dear Colleagues,

Due to their high binding specificity, monoclonal antibodies (mAbs) embody the promise of precision medicine for treating patients with tumors. Antibodies recognizing tumor-restricted antigens have been explored in clinical trials. These have shown relatively limited response rates in unselected patient populations, most likely due to activation of alternative compensatory pathways and inter-/intratumoral heterogeneity in receptor expression and mutational status, associated with higher risk of local and systemic relapse.
There is an urgent unmet need for new antigen targets and modification of mAbs. The discovery of novel antigen targets, as well as the development of single-domain antibodies (nanobodies), bispecific antibodies and antibody–drug conjugates (ADCs) have become a focus to improve the performance of mAbs. Immunomodulatory antibodies and antibodies of alternative isotypes can also present a potential strategy to retain, recruit or differentially activate immune effector cells in tumor microenvironments, and facilitate tumor cell destruction.
This Special Issue will highlight promising mAb strategies that may provide the basis for further translational investigations, particularly for patients who do not adequately benefit from currently available treatments.

Dr. Anthony Cheung
Dr. Heather J Bax
Guest Editors

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Keywords

antibodies for cancer treatment
antibody–drug conjugates
antibody engineering
antigen target discovery
alternative antibody isotypes
bispecific antibodies
immunomodulatory antibodies
nanobodies

Published Papers (7 papers)

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Research

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25 pages, 4436 KiB

Open AccessArticle

A Novel Nanobody Precisely Visualizes Phosphorylated Histone H2AX in Living Cancer Cells under Drug-Induced Replication Stress

by Eric Moeglin, Dominique Desplancq, Audrey Stoessel, Christian Massute, Jeremy Ranniger, Alastair G. McEwen, Gabrielle Zeder-Lutz, Mustapha Oulad-Abdelghani, Manuela Chiper, Pierre Lafaye, Barbara Di Ventura, Pascal Didier, Arnaud Poterszman and Etienne Weiss

Cancers 2021, 13(13), 3317; https://doi.org/10.3390/cancers13133317 - 01 Jul 2021

Cited by 13 | Viewed by 4474

Abstract

Histone H2AX phosphorylated at serine 139 (γ-H2AX) is a hallmark of DNA damage, signaling the presence of DNA double-strand breaks and global replication stress in mammalian cells. While γ-H2AX can be visualized with antibodies in fixed cells, its detection in living cells was so far not possible. Here, we used immune libraries and phage display to isolate nanobodies that specifically bind to γ-H2AX. We solved the crystal structure of the most soluble nanobody in complex with the phosphopeptide corresponding to the C-terminus of γ-H2AX and show the atomic constituents behind its specificity. We engineered a bivalent version of this nanobody and show that bivalency is essential to quantitatively visualize γ-H2AX in fixed drug-treated cells. After labelling with a chemical fluorophore, we were able to detect γ-H2AX in a single-step assay with the same sensitivity as with validated antibodies. Moreover, we produced fluorescent nanobody-dTomato fusion proteins and applied a transduction strategy to visualize with precision γ-H2AX foci present in intact living cells following drug treatment. Together, this novel tool allows performing fast screenings of genotoxic drugs and enables to study the dynamics of this particular chromatin modification in individual cancer cells under a variety of conditions. Full article

(This article belongs to the Special Issue Antibodies in Cancer Treatment)

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17 pages, 2430 KiB

Open AccessArticle

Prospective SPECT-CT Organ Dosimetry-Driven Radiation-Absorbed Dose Escalation Using the In-111 (¹¹¹In)/Yttrium 90 (⁹⁰Y) Ibritumomab Tiuxetan (Zevalin^®) Theranostic Pair in Patients with Lymphoma at Myeloablative Dose Levels

by Richard L. Wahl, Eric C. Frey, Heather A. Jacene, Brad S. Kahl, Steven Piantadosi, Jesus A. Bianco, Richard J. Hammes, Miah Jung, Wayne Kasecamp, Bin He, George Sgouros, Ian W. Flinn and Lode J. Swinnen

Cancers 2021, 13(11), 2828; https://doi.org/10.3390/cancers13112828 - 06 Jun 2021

Cited by 9 | Viewed by 3402

Abstract

Purpose: We prospectively evaluated the feasibility of SPECT-CT/planar organ dosimetry-based radiation dose escalation radioimmunotherapy in patients with recurrent non-Hodgkin’s lymphoma using the theranostic pair of ¹¹¹In and ⁹⁰Y anti-CD20 ibritumomab tiuxetan (Zevalin^®) at myeloablative radiation-absorbed doses with autologous stem cell support. We also assessed acute non-hematopoietic toxicity and early tumor response in this two-center outpatient study. Methods: 24 patients with CD20-positive relapsed or refractory rituximab-sensitive, low-grade, mantle cell, or diffuse large-cell NHL, with normal organ function, platelet counts > 75,000/mm³, and <35% tumor involvement in the marrow were treated with Rituximab (375 mg/m²) weekly for 4 consecutive weeks, then one dose of cyclophosphamide 2.5 g/m² with filgrastim 10 mcg/kg/day until stem cell collection. Of these, 18 patients with successful stem cell collection (at least 2 × 10⁶ CD34 cells/kg) proceeded to RIT. A dosimetric administration of ¹¹¹In ibritumomab tiuxetan (185 MBq) followed by five sequential quantitative planar and one SPECT/CT scan was used to determine predicted organ radiation-absorbed dose. Two weeks later, ⁹⁰Y ibritumomab tiuxetan was administered in an outpatient setting at a cohort- and patient-specific predicted organ radiation-absorbed dose guided by a Continuous Response Assessment (CRM) methodology with the following cohorts for dose escalation: 14.8 MBq/kg, and targeted 18, 24, 28, and 30.5 Gy to the liver. Autologous stem cell infusion occurred when the estimated marrow radiation-absorbed dose rate was predicted to be <1 cGy/h. Feasibility, short-term toxicities, and tumor response were assessed. Results: Patient-specific hybrid SPECT/CT + planar organ dosimetry was feasible in all 18 cases and used to determine the patient-specific therapeutic dose and guide dose escalation (26.8 ± 7.3 MBq/kg (mean), 26.3 MBq/kg (median) of ⁹⁰Y (range: 12.1–41.4 MBq/kg)) of ibritumomab tiuxetan that was required to deliver 10 Gy to the liver. Infused stem cells engrafted rapidly. The most common treatment-related toxicities were hematological and were reversible following stem cell infusion. No significant hepatotoxicity was seen. One patient died from probable treatment-related causes—pneumonia at day 27 post-transplant. One patient at dose level 18 Gy developed myelodysplastic syndrome (MDS), 4 patients required admission post-⁹⁰Y RIT for febrile neutropenia, 16/18 patients receiving ⁹⁰Y ibritumomab tiuxetan (89%) responded to the therapy, with 13 CR (72%) and 3/18 PR (17%), at 60 days post-treatment. Two patients had progressive disease at sixty days. One patient was lost to follow-up. Median time to progression was estimated to be at least 13 months. MTD to the liver is greater than 28 Gy, but the MTD was not reached as the study was terminated due to unexpected discontinuation of availability of the therapeutic agent. Conclusions: Patient-specific outpatient ⁹⁰Y ibritumomab tiuxetan RIT with myeloablative doses of RIT up to a targeted 30.5 Gy to the liver is feasible, guided by prospective SPECT/CT + planar imaging with the theranostic pair of ¹¹¹In and ⁹⁰Y anti-CD20, with outpatient autologous stem cell transplant support. Administered activity over 5 times the standard FDA-approved activity was well-tolerated. The non-hematopoietic MTD in this study exceeds 28 Gy to the liver. Initial tumor responses were common at all dose levels. This study supports the feasibility of organ dosimetry-driven patient-specific dose escalation in the treatment of NHL with stem cell transplant and provides additional information on the radiation tolerance of the normal liver to radiopharmaceutical therapy. Full article

(This article belongs to the Special Issue Antibodies in Cancer Treatment)

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21 pages, 5254 KiB

Open AccessFeature PaperArticle

Targeting Neuropilin-1 with Nanobodies Reduces Colorectal Carcinoma Development

by Yannick De Vlaeminck, Stefano Bonelli, Robin Maximilian Awad, Maarten Dewilde, Sabrina Rizzolio, Quentin Lecocq, Evangelia Bolli, Ana Rita Santos, Damya Laoui, Steve Schoonooghe, Luca Tamagnone, Cleo Goyvaerts, Massimiliano Mazzone, Karine Breckpot and Jo A. Van Ginderachter

Cancers 2020, 12(12), 3582; https://doi.org/10.3390/cancers12123582 - 30 Nov 2020

Cited by 22 | Viewed by 3876

Abstract

Neuropilin-1 (NRP-1) is a co-receptor for semaphorins and vascular endothelial growth factor (VEGF) family members that can be expressed on cancer cells and tumor-infiltrating myeloid, endothelial and lymphoid cells. It has been linked to a tumor-promoting environment upon interaction with semaphorin 3A (Sema3A). Nanobodies (Nbs) targeting NRP-1 were generated for their potential to hamper the NRP-1/Sema3A interaction and their impact on colorectal carcinoma (CRC) development was evaluated in vivo through the generation of anti-NRP-1-producing CRC cells. We observed that tumor growth was significantly delayed and survival prolonged when the anti-NRP-1 Nbs were produced in vivo. We further analyzed the tumor microenvironment and observed that the pro-inflammatory MHC-II^high/trophic MHC-II^low macrophage ratio was increased in tumors that produce anti-NRP-1 Nbs. This finding was corroborated by an increase in the expression of genes associated with MHC-II^high macrophages and a decrease in the expression of MHC-II^low macrophage-associated genes in the macrophage pool sorted from anti-NRP-1 Nb-producing tumors. Moreover, we observed a significantly higher percentage of tumor-associated antigen-specific CD8⁺ T cells in tumors producing anti-NRP-1 Nbs. These data demonstrate that an intratumoral expression of NRP-1/Sema3A blocking biologicals increases anti-tumor immunity. Full article

(This article belongs to the Special Issue Antibodies in Cancer Treatment)

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14 pages, 20343 KiB

Open AccessArticle

Therapeutic Efficacy of GC1118, a Novel Anti-EGFR Antibody, against Glioblastoma with High EGFR Amplification in Patient-Derived Xenografts

by Kyoungmin Lee, Harim Koo, Yejin Kim, Donggeon Kim, Eunju Son, Heekyoung Yang, Yangmi Lim, Minkyu Hur, Hye Won Lee, Seung Won Choi and Do-Hyun Nam

Cancers 2020, 12(11), 3210; https://doi.org/10.3390/cancers12113210 - 31 Oct 2020

Cited by 10 | Viewed by 3355

Abstract

We aimed to evaluate the preclinical efficacy of GC1118, a novel anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), against glioblastoma (GBM) tumors using patient-derived xenograft (PDX) models. A total of 15 distinct GBM PDX models were used to evaluate the therapeutic efficacy of GC1118. Genomic data derived from PDX models were analyzed to identify potential biomarkers associated with the anti-tumor efficacy of GC1118. A patient-derived cell-based high-throughput drug screening assay was performed to further validate the efficacy of GC1118. Compared to cetuximab, GC1118 exerted comparable growth inhibitory effects on the GBM tumors in the PDX models. We confirmed that GC1118 accumulated within the tumor by crossing the blood–brain barrier in in vivo specimens and observed the survival benefit in GC1118-treated intracranial models. Genomic analysis revealed high EGFR amplification as a potent biomarker for predicting the therapeutic efficacy of GC1118 in GBM tumors. In summary, GC1118 exerted a potent anti-tumor effect on GBM tumors in PDX models, and its therapeutic efficacy was especially pronounced in the tumors with high EGFR amplification. Our study supports the importance of patient stratification based on EGFR copy number variation in clinical trials for GBM. The superiority of GC1118 over other EGFR mAbs in GBM tumors should be assessed in future studies. Full article

(This article belongs to the Special Issue Antibodies in Cancer Treatment)

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18 pages, 2895 KiB

Open AccessArticle

Targeting Vesicular LGALS3BP by an Antibody-Drug Conjugate as Novel Therapeutic Strategy for Neuroblastoma

by Emily Capone, Alessia Lamolinara, Fabio Pastorino, Roberta Gentile, Sara Ponziani, Giulia Di Vittorio, Daniela D’Agostino, Sandra Bibbò, Cosmo Rossi, Enza Piccolo, Valentina Iacobelli, Rossano Lattanzio, Valeria Panella, Michele Sallese, Vincenzo De Laurenzi, Francesco Giansanti, Arturo Sala, Manuela Iezzi, Mirco Ponzoni, Rodolfo Ippoliti, Stefano Iacobelli and Gianluca Sala Show full author list Hide full author list

Cancers 2020, 12(10), 2989; https://doi.org/10.3390/cancers12102989 - 15 Oct 2020

Cited by 17 | Viewed by 4081

Abstract

Neuroblastoma is the most common extra-cranial solid tumor in infants and children, which accounts for approximately 15% of all cancer-related deaths in the pediatric population. New therapeutic modalities are urgently needed. Antibody-Drug Conjugates (ADC)s-based therapy has been proposed as potential strategy to treat this pediatric malignancy. LGALS3BP is a highly glycosylated protein involved in tumor growth and progression. Studies have shown that LGALS3BP is enriched in extracellular vesicles (EV)s derived by most neuroblastoma cells, where it plays a critical role in preparing a favorable tumor microenvironment (TME) through direct cross talk between cancer and stroma cells. Here, we describe the development of a non-internalizing LGALS3BP ADC, named 1959-sss/DM3, which selectively targets LGALS3BP expressing neuroblastoma. 1959-sss/DM3 mediated potent therapeutic activity in different types of neuroblastoma models. Notably, we found that treatments were well tolerated at efficacious doses that were fully curative. These results offer preclinical proof-of-concept for an ADC targeting exosomal LGALS3BP approach for neuroblastomas. Full article

(This article belongs to the Special Issue Antibodies in Cancer Treatment)

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Review

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17 pages, 1475 KiB

Open AccessReview

Insights from IgE Immune Surveillance in Allergy and Cancer for Anti-Tumour IgE Treatments

by Alex J. McCraw, Jitesh Chauhan, Heather J. Bax, Chara Stavraka, Gabriel Osborn, Melanie Grandits, Jacobo López-Abente, Debra H. Josephs, James Spicer, Gerd K. Wagner, Sophia N. Karagiannis, Alicia Chenoweth and Silvia Crescioli

Cancers 2021, 13(17), 4460; https://doi.org/10.3390/cancers13174460 - 04 Sep 2021

Cited by 16 | Viewed by 5035

Abstract

IgE, the predominant antibody class of the allergic response, is known for its roles in protecting against parasites; however, a growing body of evidence indicates a significant role for IgE and its associated effector cells in tumour immunosurveillance, highlighted by the field of AllergoOncology and the successes of the first-in-class IgE cancer therapeutic MOv18. Supporting this concept, substantial epidemiological data ascribe potential roles for IgE, allergy, and atopy in protecting against specific tumour types, with a corresponding increased cancer risk associated with IgE immunodeficiency. Here, we consider how epidemiological data in combination with functional data reveals a complex interplay of IgE and allergy with cancer, which cannot be explained solely by one of the existing conventional hypotheses. We furthermore discuss how, in turn, such data may be used to inform future therapeutic approaches, including the clinical management of different patient groups. With epidemiological findings highlighting several high-risk cancer types protected against by high IgE levels, it is possible that use of IgE-based therapeutics for a range of malignant indications may offer efficacy to complement that of established IgG-class antibodies. Full article

(This article belongs to the Special Issue Antibodies in Cancer Treatment)

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24 pages, 1286 KiB

Open AccessReview

Harnessing CD16-Mediated NK Cell Functions to Enhance Therapeutic Efficacy of Tumor-Targeting mAbs

by Cristina Capuano, Chiara Pighi, Simone Battella, Davide De Federicis, Ricciarda Galandrini and Gabriella Palmieri

Cancers 2021, 13(10), 2500; https://doi.org/10.3390/cancers13102500 - 20 May 2021

Cited by 35 | Viewed by 8046

Abstract

Natural killer (NK) cells hold a pivotal role in tumor-targeting monoclonal antibody (mAb)-based activity due to the expression of CD16, the low-affinity receptor for IgG. Indeed, beyond exerting cytotoxic function, activated NK cells also produce an array of cytokines and chemokines, through which they interface with and potentiate adaptive immune responses. Thus, CD16-activated NK cells can concur to mAb-dependent “vaccinal effect”, i.e., the development of antigen-specific responses, which may be highly relevant in maintaining long-term protection of treated patients. On this basis, the review will focus on strategies aimed at potentiating NK cell-mediated antitumor functions in tumor-targeting mAb-based regimens, represented by (a) mAb manipulation strategies, aimed at augmenting recruitment and efficacy of NK cells, such as Fc-engineering, and the design of bi- or trispecific NK cell engagers and (b) the possible exploitation of memory NK cells, whose distinctive characteristics (enhanced responsiveness to CD16 engagement, longevity, and intrinsic resistance to the immunosuppressive microenvironment) may maximize therapeutic mAb antitumor efficacy. Full article

(This article belongs to the Special Issue Antibodies in Cancer Treatment)

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