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11 pages, 2273 KiB

Open AccessArticle

Design and Validation of Linkers for Site-Specific Preparation of Antibody–Drug Conjugates Carrying Multiple Drug Copies Per Cysteine Conjugation Site

by Amit Kumar, Shenlan Mao, Nazzareno Dimasi and Changshou Gao

Int. J. Mol. Sci. 2020, 21(18), 6882; https://doi.org/10.3390/ijms21186882 - 19 Sep 2020

Cited by 10 | Viewed by 3658

Abstract

First-generation cysteine-based site-specific antibody–drug conjugates (ADCs) are limited to one drug per cysteine. However, certain applications require a high drug to antibody ratio (DAR), such as when low-potency payloads are used. Higher drug load can be achieved using classical cysteine conjugation methods, but [...] Read more.

First-generation cysteine-based site-specific antibody–drug conjugates (ADCs) are limited to one drug per cysteine. However, certain applications require a high drug to antibody ratio (DAR), such as when low-potency payloads are used. Higher drug load can be achieved using classical cysteine conjugation methods, but these result in heterogeneity, suboptimal efficacy and pharmacokinetics. Here, we describe the design, synthesis and validation of heterobifunctional linkers that can be used for the preparation of ADCs with a DAR of two, three and four in a site-specific manner per single cysteine conjugation site, resulting in site-specific ADCs with a DAR of four, six and eight. The designed linkers carry a sulfhydryl-specific iodoacetyl reactive group, and multiple cyclic diene moieties which can efficiently react with maleimide-carrying payloads through the Diels–Alder reaction. As a proof of concept, we synthesized site-specific DAR four, six and eight ADCs carrying tubulysin (AZ13601508) using engineered antibodies with a cysteine inserted after position 239 in the antibody CH2 domain. We evaluated and compared the in vitro cytotoxicity of ADCs obtained via the site-specific platform described herein, with ADCs prepared using classical cysteine conjugation. Our data validated a novel cysteine-based conjugation platform for the preparation of site-specific ADCs with high drug load for therapeutic applications. Full article

(This article belongs to the Special Issue Monoclonal Antibodies to Treat Cancer)

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16 pages, 1441 KiB

Open AccessArticle

Pharmacogenetics in Model-Based Optimization of Bevacizumab Therapy for Metastatic Colorectal Cancer

by Apostolos Papachristos, Eleni Karatza, Haralabos Kalofonos and Gregory Sivolapenko

Int. J. Mol. Sci. 2020, 21(11), 3753; https://doi.org/10.3390/ijms21113753 - 26 May 2020

Cited by 8 | Viewed by 3012

Abstract

Vascular endothelial growth factor A (VEGF-A) and intercellular adhesion molecule 1 (ICAM-1) are significant regulators of angiogenesis, an important biological process involved in carcinogenesis. Bevacizumab, an anti-VEGF monoclonal antibody (MAB), is approved for the treatment of metastatic Colorectal cancer (mCRC), however clinical outcomes [...] Read more.

Vascular endothelial growth factor A (VEGF-A) and intercellular adhesion molecule 1 (ICAM-1) are significant regulators of angiogenesis, an important biological process involved in carcinogenesis. Bevacizumab, an anti-VEGF monoclonal antibody (MAB), is approved for the treatment of metastatic Colorectal cancer (mCRC), however clinical outcomes are highly variable. In the present study, we developed a pharmacokinetic (PK), a simplified quasi-steady state (QSS) and a pharmacokinetic/pharmacodynamic (PK/PD) model to identify potential sources of variability. A total of 46 mCRC patients, who received bevacizumab in combination with chemotherapy were studied. VEGF-A (rs2010963, rs1570360, rs699947) and ICAM-1 (rs5498, rs1799969) genes’ polymorphisms, age, gender, weight, and dosing scheme were investigated as possible co-variates of the model’s parameters. Polymorphisms, trough, and peak levels of bevacizumab, and free VEGF-A were determined in whole blood and serum. Data were analyzed using nonlinear mixed-effects modeling. The two-compartment PK model showed that clearance (CL) was significantly lower in patients with mutant ICAM-1 rs1799969 (p < 0.0001), inter-compartmental clearance (Q) was significantly higher with mutant VEGF-A rs1570360 (p < 0.0001), and lower in patients with mutant VEGF-A rs699947 (p < 0.0001). The binding QSS model also showed that mutant ICAM-1 rs1799969 was associated with a lower CL (p = 0.0177). Mutant VEGF-A rs699947 was associated with a lower free VEGF-A levels, prior to the next dose (p = 0.000445). The above results were confirmed by the PK/PD model. Findings of the present study indicated that variants of the genes regulating angiogenesis might affect PK and PD characteristics of bevacizumab, possibly influencing the clinical outcomes. Full article

(This article belongs to the Special Issue Monoclonal Antibodies to Treat Cancer)

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Review

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28 pages, 1429 KiB

Open AccessReview

Principles and Current Clinical Landscape of Multispecific Antibodies against Cancer

by Mariam Elshiaty, Hannah Schindler and Petros Christopoulos

Int. J. Mol. Sci. 2021, 22(11), 5632; https://doi.org/10.3390/ijms22115632 - 26 May 2021

Cited by 52 | Viewed by 14374

Abstract

Building upon the resounding therapeutic success of monoclonal antibodies, and supported by accelerating progress in engineering methods, the field of multispecific therapeutic antibodies is growing rapidly. Over 140 different molecules are currently in clinical testing, with excellent results in recent phase 1–3 clinical [...] Read more.

Building upon the resounding therapeutic success of monoclonal antibodies, and supported by accelerating progress in engineering methods, the field of multispecific therapeutic antibodies is growing rapidly. Over 140 different molecules are currently in clinical testing, with excellent results in recent phase 1–3 clinical trials for several of them. Multivalent bispecific IgG-modified formats predominate today, with a clear tendency for more target antigens and further increased valency in newer constructs. The strategies to augment anticancer efficacy are currently equally divided between disruption of multiple surface antigens, and additional redirection of cytotoxic T or NK lymphocytes against the tumor. Both effects complement other modern modalities, such as tyrosine kinase inhibitors and adoptive cell therapies, with which multispecifics are increasingly applied in combination or merged, for example, in the form of antibody producing CAR-T cells and oncolytics. While mainly focused on B-cell malignancies early on, the contemporary multispecific antibody sector accommodates twice as many trials against solid compared to hematologic cancers. An exciting emerging prospect is the targeting of intracellular neoantigens using T-cell receptor (TCR) fusion proteins or TCR-mimic antibody fragments. Considering the fact that introduction of PD-(L)1 inhibitors only a few years ago has already facilitated 5-year survival rates of 30–50% for per se highly lethal neoplasms, such as metastatic melanoma and non-small-cell lung carcinoma, the upcoming enforcement of current treatments with “next-generation” immunotherapeutics, offers a justified hope for the cure of some advanced cancers in the near future. Full article

(This article belongs to the Special Issue Monoclonal Antibodies to Treat Cancer)

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16 pages, 1279 KiB

Open AccessReview

CD37 in B Cell Derived Tumors—More than Just a Docking Point for Monoclonal Antibodies

by Malgorzata Bobrowicz, Matylda Kubacz, Aleksander Slusarczyk and Magdalena Winiarska

Int. J. Mol. Sci. 2020, 21(24), 9531; https://doi.org/10.3390/ijms21249531 - 15 Dec 2020

Cited by 14 | Viewed by 4880

Abstract

CD37 is a tetraspanin expressed prominently on the surface of B cells. It is an attractive molecular target exploited in the immunotherapy of B cell-derived lymphomas and leukemia. Currently, several monoclonal antibodies targeting CD37 as well as chimeric antigen receptor-based immunotherapies are being [...] Read more.

CD37 is a tetraspanin expressed prominently on the surface of B cells. It is an attractive molecular target exploited in the immunotherapy of B cell-derived lymphomas and leukemia. Currently, several monoclonal antibodies targeting CD37 as well as chimeric antigen receptor-based immunotherapies are being developed and investigated in clinical trials. Given the unique role of CD37 in the biology of B cells, it seems that CD37 constitutes more than a docking point for monoclonal antibodies, and targeting this molecule may provide additional benefit to relapsed or refractory patients. In this review, we aimed to provide an extensive overview of the function of CD37 in B cell malignancies, providing a comprehensive view of recent therapeutic advances targeting CD37 and delineating future perspectives. Full article

(This article belongs to the Special Issue Monoclonal Antibodies to Treat Cancer)

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20 pages, 680 KiB

Open AccessReview

Monoclonal Antibodies to Treat Multiple Myeloma: A Dream Come True

by Mattia D’Agostino, Salvatore Innorcia, Mario Boccadoro and Sara Bringhen

Int. J. Mol. Sci. 2020, 21(21), 8192; https://doi.org/10.3390/ijms21218192 - 1 Nov 2020

Cited by 14 | Viewed by 8793

Abstract

Immunotherapy is increasingly used in the treatment of multiple myeloma (MM). Monoclonal antibodies (mAbs) are safe and effective ways to elicit immunotherapeutic responses. In 2015, daratumumab has become the first mAb approved by the Food and Drug Administration for clinical use in MM [...] Read more.

Immunotherapy is increasingly used in the treatment of multiple myeloma (MM). Monoclonal antibodies (mAbs) are safe and effective ways to elicit immunotherapeutic responses. In 2015, daratumumab has become the first mAb approved by the Food and Drug Administration for clinical use in MM and, in the last 5 years, a lot of clinical and preclinical research has been done to optimize the use of this drug class. Currently, mAbs have already become part of standard-of-care combinations for the treatment of relapsed/refractory MM and very soon they will also be used in the frontline setting. The success of simple mAbs (‘naked mAbs’) prompted the development of new types of molecules. Antibody–drug conjugates (ADCs) are tumor-targeting mAbs that release a cytotoxic payload into the tumor cells upon antigen binding in order to destroy them. Bispecific antibodies (BiAbs) are mAbs simultaneously targeting a tumor-associated antigen and an immune cell-associated antigen in order to redirect the immune cell cytotoxicity against the tumor cell. These different constructs produced solid preclinical data and promising clinical data in phase I/II trials. The aim of this review article is to summarize all the recent developments in the field, including data on naked mAbs, ADCs and BiAbs. Full article

(This article belongs to the Special Issue Monoclonal Antibodies to Treat Cancer)

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17 pages, 632 KiB

Open AccessReview

Greatest Hits—Innovative Technologies for High Throughput Identification of Bispecific Antibodies

by Tim Hofmann, Simon Krah, Carolin Sellmann, Stefan Zielonka and Achim Doerner

Int. J. Mol. Sci. 2020, 21(18), 6551; https://doi.org/10.3390/ijms21186551 - 8 Sep 2020

Cited by 8 | Viewed by 6646

Abstract

Recent years have shown a tremendous increase and diversification in antibody-based therapeutics with advances in production techniques and formats. The plethora of currently investigated bi- to multi-specific antibody architectures can be harnessed to elicit a broad variety of specific modes of actions in [...] Read more.

Recent years have shown a tremendous increase and diversification in antibody-based therapeutics with advances in production techniques and formats. The plethora of currently investigated bi- to multi-specific antibody architectures can be harnessed to elicit a broad variety of specific modes of actions in oncology and immunology, spanning from enhanced selectivity to effector cell recruitment, all of which cannot be addressed by monospecific antibodies. Despite continuously growing efforts and methodologies, the identification of an optimal bispecific antibody as the best possible combination of two parental monospecific binders, however, remains challenging, due to tedious cloning and production, often resulting in undesired extended development times and increased expenses. Although automated high throughput screening approaches have matured for pharmaceutical small molecule development, it was only recently that protein bioconjugation technologies have been developed for the facile generation of bispecific antibodies in a ‘plug and play’ manner. In this review, we provide an overview of the most relevant methodologies for bispecific screening purposes—the DuoBody concept, paired light chain single cell production approaches, Sortase A and Transglutaminase, the SpyTag/SpyCatcher system, and inteins—and elaborate on the benefits as well as drawbacks of the different technologies. Full article

(This article belongs to the Special Issue Monoclonal Antibodies to Treat Cancer)

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12 pages, 806 KiB

Open AccessReview

Immune-Driven Pathogenesis of Neurotoxicity after Exposure of Cancer Patients to Immune Checkpoint Inhibitors

by Noelia Vilariño, Jordi Bruna, Foteini Kalofonou, Garifallia G. Anastopoulou and Andreas A. Argyriou

Int. J. Mol. Sci. 2020, 21(16), 5774; https://doi.org/10.3390/ijms21165774 - 11 Aug 2020

Cited by 24 | Viewed by 3097

Abstract

Over the last decade, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several cancer types. ICIs work through the blockage of immune inhibitory signals, while increasing the T-cell specific immune antitumoral response. However, due to the fact that ICIs’ mechanism of action [...] Read more.

Over the last decade, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several cancer types. ICIs work through the blockage of immune inhibitory signals, while increasing the T-cell specific immune antitumoral response. However, due to the fact that ICIs’ mechanism of action is not tissue antigen-specific and not limited to the tumor microenvironment, the use of cancer immunotherapy can produce a broad range of immune-related adverse events (irAEs). Neurological immune-related adverse events (NirAEs) are rare (the overall incidence varies between 1% to 6%), and these adverse events mainly concern the peripheral nervous system, rather than the central nervous system. Due to their potential severity, which could cause interruptions to cancer treatment, NirAEs are of particular clinical importance. Currently, the pathogenesis of these complications is not completely understood, although T-cells seem to play a principal role. Nevertheless, the development of NirAEs is likely to be a multifactorial and complex process. This conclusion can be extracted from the wide range of neurological auto-inflammatory and autoimmune disorders triggered or exacerbated by ICIs, and the extensive variability of the limited histological findings reported. The aim of this review is to summarize the potential immune-driven pathological mechanisms of NirAEs. Full article

(This article belongs to the Special Issue Monoclonal Antibodies to Treat Cancer)

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29 pages, 1762 KiB

Open AccessReview

Immunotherapies and Combination Strategies for Immuno-Oncology

by Cody Barbari, Tyler Fontaine, Priyanka Parajuli, Narottam Lamichhane, Silvia Jakubski, Purushottam Lamichhane and Rahul R. Deshmukh

Int. J. Mol. Sci. 2020, 21(14), 5009; https://doi.org/10.3390/ijms21145009 - 15 Jul 2020

Cited by 56 | Viewed by 8017

Abstract

The advent of novel immunotherapies in the treatment of cancers has dramatically changed the landscape of the oncology field. Recent developments in checkpoint inhibition therapies, tumor-infiltrating lymphocyte therapies, chimeric antigen receptor T cell therapies, and cancer vaccines have shown immense promise for significant [...] Read more.

The advent of novel immunotherapies in the treatment of cancers has dramatically changed the landscape of the oncology field. Recent developments in checkpoint inhibition therapies, tumor-infiltrating lymphocyte therapies, chimeric antigen receptor T cell therapies, and cancer vaccines have shown immense promise for significant advancements in cancer treatments. Immunotherapies act on distinct steps of immune response to augment the body’s natural ability to recognize, target, and destroy cancerous cells. Combination treatments with immunotherapies and other modalities intend to activate immune response, decrease immunosuppression, and target signaling and resistance pathways to offer a more durable, long-lasting treatment compared to traditional therapies and immunotherapies as monotherapies for cancers. This review aims to briefly describe the rationale, mechanisms of action, and clinical efficacy of common immunotherapies and highlight promising combination strategies currently approved or under clinical development. Additionally, we will discuss the benefits and limitations of these immunotherapy approaches as monotherapies as well as in combination with other treatments. Full article

(This article belongs to the Special Issue Monoclonal Antibodies to Treat Cancer)

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18 pages, 884 KiB

Open AccessReview

Rheumatic Manifestations in Patients Treated with Immune Checkpoint Inhibitors

by Konstantinos Melissaropoulos, Kalliopi Klavdianou, Alexandra Filippopoulou, Fotini Kalofonou, Haralabos Kalofonos and Dimitrios Daoussis

Int. J. Mol. Sci. 2020, 21(9), 3389; https://doi.org/10.3390/ijms21093389 - 11 May 2020

Cited by 19 | Viewed by 4018

Abstract

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that activate the immune system, aiming at enhancing antitumor immunity. Their clinical efficacy is well-documented, but the side effects associated with their use are still under investigation. These drugs cause several immune-related adverse events (ir-AEs), some [...] Read more.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that activate the immune system, aiming at enhancing antitumor immunity. Their clinical efficacy is well-documented, but the side effects associated with their use are still under investigation. These drugs cause several immune-related adverse events (ir-AEs), some of which stand within the field of rheumatology. Herein, we present a literature review performed in an effort to evaluate all publicly available clinical data regarding rheumatic manifestations associated with ICIs. The most common musculoskeletal ir-AEs are inflammatory arthritis, polymyalgia rheumatica and myositis. Non-musculoskeletal rheumatic manifestations are less frequent, with the most prominent being sicca, vasculitides and sarcoidosis. Cases of systemic lupus erythematosus or scleroderma are extremely rare. The majority of musculoskeletal ir-AEs are of mild/moderate severity and can be managed with steroids with no need for ICI discontinuation. In severe cases, more intense immunosuppressive therapy and permanent ICI discontinuation may be employed. Oncologists should periodically screen patients receiving ICIs for new-onset inflammatory musculoskeletal complaints and seek a rheumatology consultation in cases of persisting symptoms. Full article

(This article belongs to the Special Issue Monoclonal Antibodies to Treat Cancer)

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