Antibody-Based Therapeutics for Treating Cancer

A special issue of Antibodies (ISSN 2073-4468).

Deadline for manuscript submissions: closed (1 September 2019) | Viewed by 29528

Special Issue Editors


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Guest Editor
Chief, Division of Hematology Oncology, Mays Family Foundation Distinguished Chair in Oncology, University of Texas Health, San Antonio, 7979 Wurzbach Road, San Antonio, TX 78229, USA
Interests: drug discovery; translational drug development; drug resistance; early phase clinical trials; pancreatic cancer; gastrointestinal stromal tumor; lymphoma; chronic lymphocytic leukemia

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Guest Editor
1. Cleveland Clinic, 9500 Euclid Ave, CA60, Cleveland, OH 44195, USA
2. Taussig Cancer Center, 10201 Carnegie Ave, Cleveland, OH 44195, USA
Interests: anti-cancer therapies

Special Issue Information

Dear Colleagues,

Therapeutic monoclonal antibodies (Mabs) targeting oncogenic cell surface receptors on tumor cells and cells of the tumor microenvironment are an important therapeutic modality in both solid and hematologic malignancies. These targets include secreted ligands (e.g., VEGF and HGH), their receptors (e.g., HER1, VEGFR2, CD20), immune checkpoints and their ligands (e.g., PD-1 and PD-L1) immune activators (e.g. CD40, OX40) and antibody drug conjugates (e.g. TDM-1). The ability to genetically engineer the structure/functions of Mabs provides novel ways to improve their efficacy and safety. Multi-omics technologies and immune monitoring have allowed serial sampling of tumor and blood/serum to better understand response and resistance to therapy in addition to deciphering of complex signaling networks that drive oncogenic resistance.

This Special Issue of Antibodies focuses on disease specific USFDA approval of therapeutic Mabs for solid and hematologic malignancies. In addition, novel immune checkpoint inhibiting and activating Mabs for disease specific and tumor agnostic indications will also be discussed. In addition, safety, tolerability and side effects will also be reviewed. Finally, we also discuss promising novel Mabs in early- and late-phase clinical trials, likely to impact disease elimination and improve survival.

Prof. Daruka Mahadevan
Dr. Faiz Anwer
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. Antibodies is an international peer-reviewed open access quarterly 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

  • Anti-Cancer Therapeutic Antibodies
  • Immune checkpoint Antibodies
  • Antibody Drug Conjugates
  • Combination Therapies

Published Papers (4 papers)

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Research

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20 pages, 3834 KiB  
Article
Antibody-Drug Conjugates Targeting the Urokinase Receptor (uPAR) as a Possible Treatment of Aggressive Breast Cancer
by Efrat T. Harel, Penelope M. Drake, Robyn M. Barfield, Irene Lui, Shauna Farr-Jones, Laura Van’t Veer, Zev J. Gartner, Evan M. Green, André Luiz Lourenço, Yifan Cheng, Byron C. Hann, David Rabuka and Charles S. Craik
Antibodies 2019, 8(4), 54; https://doi.org/10.3390/antib8040054 - 05 Nov 2019
Cited by 19 | Viewed by 7955
Abstract
A promising molecular target for aggressive cancers is the urokinase receptor (uPAR). A fully human, recombinant antibody that binds uPAR to form a stable complex that blocks uPA-uPAR interactions (2G10) and is internalized primarily through endocytosis showed efficacy in a mouse xenograft model [...] Read more.
A promising molecular target for aggressive cancers is the urokinase receptor (uPAR). A fully human, recombinant antibody that binds uPAR to form a stable complex that blocks uPA-uPAR interactions (2G10) and is internalized primarily through endocytosis showed efficacy in a mouse xenograft model of highly aggressive, triple negative breast cancer (TNBC). Antibody-drug conjugates (ADCs) of 2G10 were designed and produced bearing tubulin inhibitor payloads ligated through seven different linkers. Aldehyde tag technology was employed for linking, and either one or two tags were inserted into the antibody heavy chain, to produce site-specifically conjugated ADCs with drug-to-antibody ratios of either two or four. Both cleavable and non-cleavable linkers were combined with two different antimitotic toxins—MMAE (monomethylauristatin E) and maytansine. Nine different 2G10 ADCs were produced and tested for their ability to target uPAR in cell-based assays and a mouse model. The anti-uPAR ADC that resulted in tumor regression comprised an MMAE payload with a cathepsin B cleavable linker, 2G10-RED-244-MMAE. This work demonstrates in vitro activity of the 2G10-RED-244-MMAE in TNBC cell lines and validates uPAR as a therapeutic target for TNBC. Full article
(This article belongs to the Special Issue Antibody-Based Therapeutics for Treating Cancer)
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16 pages, 2822 KiB  
Article
Optimization of an Antibody Light Chain Framework Enhances Expression, Biophysical Properties and Pharmacokinetics
by Patrice Douillard, Michael Freissmuth, Gerhard Antoine, Michael Thiele, Daniel Fleischanderl, Peter Matthiessen, Dirk Voelkel, Randolf J. Kerschbaumer, Friedrich Scheiflinger and Nicolas Sabarth
Antibodies 2019, 8(3), 46; https://doi.org/10.3390/antib8030046 - 06 Sep 2019
Cited by 5 | Viewed by 6188
Abstract
Efficacy, safety, and manufacturability of therapeutic antibodies are influenced by their biopharmaceutical and biophysical properties. These properties can be optimized by library approaches or rationale protein design. Here, we employed a protein engineering approach to modify the variable domain of the light chain [...] Read more.
Efficacy, safety, and manufacturability of therapeutic antibodies are influenced by their biopharmaceutical and biophysical properties. These properties can be optimized by library approaches or rationale protein design. Here, we employed a protein engineering approach to modify the variable domain of the light chain (VL) framework of an oxidized macrophage migration inhibitory factor (oxMIF)-specific antibody. The amendment of the antibody sequence was based on homology to human germline VL genes. Three regions or positions were identified in the VL domain—L1-4, L66, L79—and mutated independently or in combination to match the closest germline V gene. None of the mutations altered oxMIF specificity or affinity, but some variants improved thermal stability, aggregation propensity, and resulted in up to five-fold higher expression. Importantly, the improved biopharmaceutical properties translated into a superior pharmacokinetic profile of the antibody. Thus, optimization of the V domain framework can ameliorate the biophysical qualities of a therapeutic antibody candidate, and as result its manufacturability, and also has the potential to improve pharmacokinetics. Full article
(This article belongs to the Special Issue Antibody-Based Therapeutics for Treating Cancer)
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Review

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54 pages, 3602 KiB  
Review
Therapeutic Monoclonal Antibodies Targeting Immune Checkpoints for the Treatment of Solid Tumors
by Nicholas Gravbrot, Kacy Gilbert-Gard, Paras Mehta, Yarah Ghotmi, Madhulika Banerjee, Christopher Mazis and Srinath Sundararajan
Antibodies 2019, 8(4), 51; https://doi.org/10.3390/antib8040051 - 21 Oct 2019
Cited by 28 | Viewed by 8060
Abstract
Recently, modulation of immune checkpoints has risen to prominence as a means to treat a number of solid malignancies, given the durable response seen in many patients and improved side effect profile compared to conventional chemotherapeutic agents. Several classes of immune checkpoint modulators [...] Read more.
Recently, modulation of immune checkpoints has risen to prominence as a means to treat a number of solid malignancies, given the durable response seen in many patients and improved side effect profile compared to conventional chemotherapeutic agents. Several classes of immune checkpoint modulators have been developed. Here, we review current monoclonal antibodies directed against immune checkpoints that are employed in practice today. We discuss the history, mechanism, indications, and clinical data for each class of therapies. Furthermore, we review the challenges to durable tumor responses that are seen in some patients and discuss possible interventions to circumvent these barriers. Full article
(This article belongs to the Special Issue Antibody-Based Therapeutics for Treating Cancer)
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25 pages, 906 KiB  
Review
Investigational Monoclonal Antibodies in the Treatment of Multiple Myeloma: A Systematic Review of Agents under Clinical Development
by Ahmad Iftikhar, Hamza Hassan, Nimra Iftikhar, Adeela Mushtaq, Atif Sohail, Nathaniel Rosko, Rajshekhar Chakraborty, Faryal Razzaq, Sonia Sandeep, Jason Neil Valent, Abraham Sebastian Kanate and Faiz Anwer
Antibodies 2019, 8(2), 34; https://doi.org/10.3390/antib8020034 - 24 May 2019
Cited by 12 | Viewed by 6766
Abstract
Background: Immunotherapy for multiple myeloma (MM) has been the focus in recent years due to its myeloma-specific immune responses. We reviewed the literature on non-Food and Drug Administration (FDA) approved monoclonal antibodies (mAbs) to highlight future perspectives. We searched PubMed, EMBASE, Web of [...] Read more.
Background: Immunotherapy for multiple myeloma (MM) has been the focus in recent years due to its myeloma-specific immune responses. We reviewed the literature on non-Food and Drug Administration (FDA) approved monoclonal antibodies (mAbs) to highlight future perspectives. We searched PubMed, EMBASE, Web of Science, Cochrane Library and ClinicalTrials.gov to include phase I/II clinical trials. Data from 39 studies (1906 patients) were included. Of all the agents, Isatuximab (Isa, anti-CD38) and F50067 (anti-CXCR4) were the only mAbs to produce encouraging results as monotherapy with overall response rates (ORRs) of 66.7% and 32% respectively. Isa showed activity when used in combination with lenalidomide (Len) and dexamethasone (Dex), producing a clinical benefit rate (CBR) of 83%. Additionally, Isa used in combination with pomalidomide (Pom) and Dex resulted in a CBR of 73%. Indatuximab Ravtansine (anti-CD138 antibody-drug conjugate) produced an ORR of 78% and 79% when used in combination with Len-Dex and Pom-Dex, respectively. Conclusions: Combination therapy using mAbs such as indatuximab, pembrolizumab, lorvotuzumab, siltuximab or dacetuzumab with chemotherapy agents produced better outcomes as compared to monotherapies. Further clinical trials investigating mAbs targeting CD38 used in combination therapy are warranted. Full article
(This article belongs to the Special Issue Antibody-Based Therapeutics for Treating Cancer)
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