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Antibodies
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Advances in Antibody–Drug Conjugates (ADCs)
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Advances in Antibody–Drug Conjugates (ADCs)

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

Deadline for manuscript submissions: closed (10 October 2021) | Viewed by 48878

Special Issue Editor

Dr. Iftekhar Mahmood

E-Mail Website
Guest Editor
Mahmood Clinical Pharmacology, Consultancy, LLC, 1709, Piccard Dr, Rockville, MD 20850, USA
Interests: clinical pharmacology aspects of therapeutic proteins; antibodies; blood products; coagulation factors; immunoglobulins; allometry; pharmacokinetics & pharmacodynamics; pediatric drug development

Special Issue Information

Antibody–drug conjugates (ADCs) are a class of pharmaceutical products designed to target cancer cells for treating a wide variety of cancers. Most of the ADCs developed or in clinical trials are for oncology and hematology indications, but there are attempts to expand the indications to other disease areas, such as inflammatory diseases, atherosclerosis, and bacteremia. The first ADC, Gemtuzumab ozogamicin (trade name: Mylotarg), for the treatment of CD33-positive acute myelogenous leukemia was approved by the USA Food and Drug Administration (FDA) in 2000. Since then, there has been an enormous focus on developing ADCS by pharmaceutical companies. Eight ADCs are currently approved by the FDA for clinical use.

ADCs are complex molecules composed of an antibody linked to a biologically active cytotoxic drug forming a conjugate. The cytotoxic drug has the ability to kill cancer cells and is designed to distinguish between healthy and cancerous cells.

In order to develop a therapeutically beneficial ADC, it is important to understand its chemistry, mechanism of action, pre-clinical pharmacology, clinical pharmacology, and safety and efficacy. Therefore, the journal Antibodies is planning a Special Issue on ADCs and is inviting experts from the aforementioned disciplines to contribute manuscripts on the different aspects of the development of ADCs.

Dr. Iftekhar Mahmood
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 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

  • Antibody–drug conjugates (ADCs) 
  • Chemistry 
  • Preclinical and clinical pharmacology 
  • Clinical (efficacy and safety)

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Published Papers (6 papers)

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Research

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18 pages, 5001 KiB  
Article
Novel Anti-FOLR1 Antibody–Drug Conjugate MORAb-202 in Breast Cancer and Non-Small Cell Lung Cancer Cells
by Yuki Matsunaga, Toshimitsu Yamaoka, Motoi Ohba, Sakiko Miura, Hiroko Masuda, Takafumi Sangai, Masafumi Takimoto, Seigo Nakamura and Junji Tsurutani
Antibodies 2021, 10(1), 6; https://doi.org/10.3390/antib10010006 - 1 Feb 2021
Cited by 19 | Viewed by 8664
Abstract
Antibody–drug conjugates (ADCs), which are currently being developed, may become promising cancer therapeutics. Folate receptor α (FOLR1), a glycosylphosphatidylinositol-anchored membrane protein, is an attractive target of ADCs, as it is largely absent from normal tissues but is overexpressed in malignant tumors of epithelial [...] Read more.
Antibody–drug conjugates (ADCs), which are currently being developed, may become promising cancer therapeutics. Folate receptor α (FOLR1), a glycosylphosphatidylinositol-anchored membrane protein, is an attractive target of ADCs, as it is largely absent from normal tissues but is overexpressed in malignant tumors of epithelial origin, including ovarian, lung, and breast cancer. In this study, we tested the effects of novel anti-FOLR1 antibody–eribulin conjugate MORAb-202 in breast cancer and non-small cell lung cancer (NSCLC) cell lines. FOLR1 expression, cell proliferation, bystander killing effects, and apoptosis were evaluated in seven breast cancer and nine NSCLC cell lines treated with MORAb-202. Tumor growth and FOLR1 expression were assessed in T47D and MCF7 orthotopic xenograft mouse models after a single intravenous administration of MORAb-202 (5 mg/kg). MORAb-202 was associated with inhibited cell proliferation, with specific selectivity toward FOLR1-expressing breast cancer cell lines. Eribulin, the payload of MORAb-202, was unleashed in HCC1954 cells, diffused into intercellular spaces, and then killed the non-FOLR1-expressing MCF7 cells in co-culture systems. In orthotopic xenograft mouse models, FOLR1-expressing T47D tumors and non-FOLR1-expressing MCF7 tumors were suppressed upon MORAb-202 administration. The novel anti-FOLR1 antibody–eribulin conjugate MORAb-202 has potential antitumor effects in breast cancer. Full article
(This article belongs to the Special Issue Advances in Antibody–Drug Conjugates (ADCs))
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13 pages, 554 KiB  
Article
Interspecies Scaling of Antibody–Drug Conjugates (ADC) for the Prediction of Human Clearance
by Iftekhar Mahmood
Antibodies 2021, 10(1), 1; https://doi.org/10.3390/antib10010001 - 7 Jan 2021
Cited by 8 | Viewed by 5066
Abstract
Allometric scaling is a useful tool for the extrapolation of pharmacokinetic parameters from animals to humans. The objective of this study was to predict human clearance of antibody–drug conjugates (ADC) allometrically from one to three animal species and compare the predicted human clearance [...] Read more.
Allometric scaling is a useful tool for the extrapolation of pharmacokinetic parameters from animals to humans. The objective of this study was to predict human clearance of antibody–drug conjugates (ADC) allometrically from one to three animal species and compare the predicted human clearance with the observed human clearance. For three animal species allometric scaling, the “Rule of Exponents” (ROE) was used. The results of the study indicated that three-species allometric scaling in association with the ROE provides acceptable prediction (within 0.5–2-fold prediction error) of human clearance. The two-species allometric scaling resulted in substantial prediction error. One-species scaling using a fixed exponent of 1.0 provided acceptable prediction error (within 0.5–2-fold) by monkey, rat, and mouse, in which monkey and rat were comparable. Overall, the predicted human clearance values of ADCs from animal(s) was good. The allometric method proposed in this article can be used to predict human clearance from the animal data and subsequently to select the first-in-human dose of ADCs. Full article
(This article belongs to the Special Issue Advances in Antibody–Drug Conjugates (ADCs))
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Review

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11 pages, 262 KiB  
Review
Introduction to Antibody-Drug Conjugates
by Mark C. Pettinato
Antibodies 2021, 10(4), 42; https://doi.org/10.3390/antib10040042 - 27 Oct 2021
Cited by 57 | Viewed by 9765
Abstract
Antibody-drug conjugates (ADCs) are innovative biopharmaceutical products in which a monoclonal antibody is linked to a small molecule drug with a stable linker. Most of the ADCs developed so far are for treating cancer, but there is enormous potential for using ADCs to [...] Read more.
Antibody-drug conjugates (ADCs) are innovative biopharmaceutical products in which a monoclonal antibody is linked to a small molecule drug with a stable linker. Most of the ADCs developed so far are for treating cancer, but there is enormous potential for using ADCs to treat other diseases. Currently, ten ADCs have been approved by the United States Food and Drug Administration (FDA), and more than 90 ADCs are under worldwide clinical development. Monoclonal antibodies have evolved from research tools to powerful therapeutics in the past 30 years. Tremendous strides have been made in antibody discovery, protein bioengineering, formulation, and delivery devices. This manuscript provides an overview of the biology, chemistry, and biophysical properties of each component of ADC design. This review summarizes the advances and challenges in the field to date, with an emphasis on antibody conjugation, linker-payload chemistry, novel payload classes, drug-antibody ratio (DAR), and product development. The review emphasizes the lessons learned in the development of oncology antibody conjugates and look towards future innovations enabling other therapeutic indications. The review discusses resistance mechanisms to ADCs, and give an opinion on future perspectives. Full article
(This article belongs to the Special Issue Advances in Antibody–Drug Conjugates (ADCs))
17 pages, 241 KiB  
Review
Effect of Intrinsic and Extrinsic Factors on the Pharmacokinetics of Antibody–Drug Conjugates (ADCs)
by Iftekhar Mahmood
Antibodies 2021, 10(4), 40; https://doi.org/10.3390/antib10040040 - 15 Oct 2021
Cited by 7 | Viewed by 5211
Abstract
Antibody–drug conjugates (ADCs) are complex molecules wherein a monoclonal antibody is linked to a biologically active drug (a small molecule), forming a conjugate. Initially, most of the ADCs were developed and are being developed for the treatment of cancer; however, with time, it [...] Read more.
Antibody–drug conjugates (ADCs) are complex molecules wherein a monoclonal antibody is linked to a biologically active drug (a small molecule), forming a conjugate. Initially, most of the ADCs were developed and are being developed for the treatment of cancer; however, with time, it has been realized that ADCs can also be developed to manage or cure other diseases. Pharmacokinetics (PK) plays an important role in modern-day drug development and the knowledge of PK is crucial in designing a safe and efficacious dose to treat a wide variety of diseases. There are several factors that can alter the PK of a drug; as a result, one has to adjust the dose in a patient population. These factors can be termed ‘intrinsic’ or ‘extrinsic’. For small molecules, the impact of both intrinsic and extrinsic factors is well established. The impact of age, gender, disease states such as renal and hepatic impairment, drug–drug interaction, food, and in many cases alcohol on the PK of small molecules are well known. On the other hand, for macromolecules, the impact of these factors is not well established. Since the ADCs are a combination product of a monoclonal antibody linked to a small molecule, both the small molecule and the monoclonal antibody of the ADCs may be subjected to many intrinsic and extrinsic factors. This review summarizes the impact of intrinsic and extrinsic factors on the PK of ADCs and the payloads. Full article
(This article belongs to the Special Issue Advances in Antibody–Drug Conjugates (ADCs))
19 pages, 258 KiB  
Review
Clinical Pharmacology of Antibody-Drug Conjugates
by Iftekhar Mahmood
Antibodies 2021, 10(2), 20; https://doi.org/10.3390/antib10020020 - 21 May 2021
Cited by 25 | Viewed by 9141
Abstract
Antibody-drug conjugates (ADCs) are biopharmaceutical products where a monoclonal antibody is linked to a biologically active drug (a small molecule) forming a conjugate. Since the approval of first ADC (Gemtuzumab ozogamicin (trade name: Mylotarg)) for the treatment of CD33-positive acute myelogenous leukemia, several [...] Read more.
Antibody-drug conjugates (ADCs) are biopharmaceutical products where a monoclonal antibody is linked to a biologically active drug (a small molecule) forming a conjugate. Since the approval of first ADC (Gemtuzumab ozogamicin (trade name: Mylotarg)) for the treatment of CD33-positive acute myelogenous leukemia, several ADCs have been developed for the treatment of cancer. The goal of an ADC as a cancer agent is to release the cytotoxic drug to kill the tumor cells without harming the normal or healthy cells. With time, it is being realized that ADCS can also be used to manage or cure other diseases such as inflammatory diseases, atherosclerosis, and bacteremia and some research in this direction is ongoing. The focus of this review is on the clinical pharmacology aspects of ADC development. From the selection of an appropriate antibody to the finished product, the entire process of the development of an ADC is a difficult and challenging task. Clinical pharmacology is one of the most important tools of drug development since this tool helps in finding the optimum dose of a product, thus preserving the safety and efficacy of the product in a patient population. Unlike other small or large molecules where only one moiety and/or metabolite(s) is generally measured for the pharmacokinetic profiling, there are several moieties that need to be measured for characterizing the PK profiles of an ADC. Therefore, knowledge and understanding of clinical pharmacology of ADCs is vital for the selection of a safe and efficacious dose in a patient population. Full article
(This article belongs to the Special Issue Advances in Antibody–Drug Conjugates (ADCs))
12 pages, 251 KiB  
Review
Considerations for the Nonclinical Safety Evaluation of Antibody–Drug Conjugates
by J. Edward Fisher, Jr.
Antibodies 2021, 10(2), 15; https://doi.org/10.3390/antib10020015 - 19 Apr 2021
Cited by 11 | Viewed by 9066
Abstract
The targeted delivery of drugs by means of linking them to antibodies (Abs) to form antibody–drug conjugates (ADCs) has become an important approach in oncology and could potentially be used in other therapeutic areas. Targeted therapy is aimed at improving clinical efficacy while [...] Read more.
The targeted delivery of drugs by means of linking them to antibodies (Abs) to form antibody–drug conjugates (ADCs) has become an important approach in oncology and could potentially be used in other therapeutic areas. Targeted therapy is aimed at improving clinical efficacy while minimizing adverse reactions. The nonclinical safety assessment of ADCs presents several unique challenges involving the need to examine a complex molecule, each component of which can contribute to the effects observed, in appropriate animal models. Some considerations for the nonclinical safety evaluation of ADCs based on a literature review of ADCs in clinical development (currently or previously) are discussed. Full article
(This article belongs to the Special Issue Advances in Antibody–Drug Conjugates (ADCs))
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