Importance and Considerations of Antibody Engineering in Antibody-Drug Conjugates Development from a Clinical Pharmacologist’s Perspective

Antibody-drug conjugates (ADCs) appear to be in a developmental boom, with five FDA approvals in the last two years and a projected market value of over $4 billion by 2024. Major advancements in the engineering of these novel cytotoxic drug carriers have provided a few early success stories. Although the use of these immunoconjugate agents are still in their infancy, valuable lessons in the engineering of these agents have been learned from both preclinical and clinical failures. It is essential to appreciate how the various mechanisms used to engineer changes in ADCs can alter the complex pharmacology of these agents and allow the ADCs to navigate the modern-day therapeutic challenges within oncology. This review provides a global overview of ADC characteristics which can be engineered to alter the interaction with the immune system, pharmacokinetic and pharmacodynamic profiles, and therapeutic index of ADCs. In addition, this review will highlight some of the engineering approaches being explored in the creation of the next generation of ADCs.

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Antibody-drug conjugates for the treatment of lymphoma: clinical advances and latest progress

Journal of Hematology & Oncology ◽

10.1186/s13045-021-01097-z ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Yurou Chu ◽

Xiangxiang Zhou ◽

Xin Wang

Keyword(s):

Therapeutic Index ◽

Essential Elements ◽

Brentuximab Vedotin ◽

Efficacy And Safety ◽

Antibody Drug Conjugates ◽

Drug Conjugates ◽

Lymphoma Treatment ◽

Novel Targets ◽

Clinical Advances ◽

Antibody Drug

AbstractAntibody-drug conjugates (ADCs) are a promising class of immunotherapies with the potential to specifically target tumor cells and ameliorate the therapeutic index of cytotoxic drugs. ADCs comprise monoclonal antibodies, cytotoxic payloads with inherent antitumor activity, and specialized linkers connecting the two. In recent years, three ADCs, brentuximab vedotin, polatuzumab vedotin, and loncastuximab tesirine, have been approved and are already establishing their place in lymphoma treatment. As the efficacy and safety of ADCs have moved in synchrony with advances in their design, a plethora of novel ADCs have garnered growing interest as treatments. In this review, we provide an overview of the essential elements of ADC strategies in lymphoma and elucidate the up-to-date progress, current challenges, and novel targets of ADCs in this rapidly evolving field.

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Antibody–Drug Conjugates for the Treatment of Breast Cancer

Cancers ◽

10.3390/cancers13122898 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2898

Author(s):

Chiara Corti ◽

Federica Giugliano ◽

Eleonora Nicolò ◽

Liliana Ascione ◽

Giuseppe Curigliano

Keyword(s):

Breast Cancer ◽

Bystander Effect ◽

Metastatic Breast ◽

Therapeutic Index ◽

Cytotoxic Agents ◽

Target Antigen ◽

Her2 Positive ◽

Antibody Drug Conjugates ◽

Drug Conjugates ◽

Antibody Drug

Metastatic breast cancer (BC) is currently an incurable disease. Besides endocrine therapy and targeted agents, chemotherapy is often used in the treatment of this disease. However, lack of tumor specificity and toxicity associated with dose exposure limit the manageability of cytotoxic agents. Antibody–drug conjugates (ADCs) are a relatively new class of anticancer drugs. By merging the selectivity of monoclonal antibodies with the cytotoxic properties of chemotherapy, they improve the therapeutic index of antineoplastic agents. Three core components characterize ADCs: the antibody, directed to a target antigen; the payload, typically a cytotoxic agent; a linker, connecting the antibody to the payload. The most studied target antigen is HER2 with some agents, such as trastuzumab deruxtecan, showing activity not only in HER2-positive, but also in HER2-low BC patients, possibly due to a bystander effect. This property to provide a cytotoxic impact also against off-target cancer cells may overcome the intratumoral heterogeneity of some target antigens. Other cancer-associated antigens represent a strategy for the development of ADCs against triple-negative BC, as shown by the recent approval of sacituzumab govitecan. In this review, we discuss the current landscape of ADC development for the treatment of BC, as well as the possible limitations of this treatment.

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Patient Selection Strategies to Maximize Therapeutic Index of Antibody–Drug Conjugates: Prior Approaches and Future Directions

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-19-0993 ◽

2020 ◽

Vol 19 (9) ◽

pp. 1770-1783

Author(s):

Marna Williams ◽

Anna Spreafico ◽

Kapil Vashisht ◽

Mary Jane Hinrichs

Keyword(s):

Patient Selection ◽

Therapeutic Index ◽

Future Directions ◽

Antibody Drug Conjugates ◽

Drug Conjugates ◽

Selection Strategies ◽

Antibody Drug

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A Polar Sulfamide Spacer Significantly Enhances the Manufacturability, Stability, and Therapeutic Index of Antibody–Drug Conjugates

Antibodies ◽

10.3390/antib7010012 ◽

2018 ◽

Vol 7 (1) ◽

pp. 12 ◽

Cited By ~ 6

Author(s):

◽

...

Keyword(s):

Therapeutic Index ◽

Antibody Drug Conjugates ◽

Drug Conjugates ◽

Antibody Drug

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Correction: Verkade, J.M.M.; et al. A Polar Sulfamide Spacer Significantly Enhances the Manufacturability, Stability, and Therapeutic Index of Antibody–Drug Conjugates. Antibodies 2018, 7, 12

Antibodies ◽

10.3390/antib7030034 ◽

2018 ◽

Vol 7 (3) ◽

pp. 34 ◽

Cited By ~ 1

Author(s):

Jorge Verkade ◽

Marloes Wijdeven ◽

Remon van Geel ◽

Brian Janssen ◽

Sander van Berkel ◽

...

Keyword(s):

Conflict Of Interest ◽

Therapeutic Index ◽

Antibody Drug Conjugates ◽

Drug Conjugates ◽

Interest Section ◽

Published Paper ◽

Antibody Drug

The conflict of interest section of the published paper [1] has been updated as follows[...]

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Antibody-Drug Conjugates: The New Frontier of Chemotherapy

International Journal of Molecular Sciences ◽

10.3390/ijms21155510 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5510 ◽

Cited By ~ 3

Author(s):

Sara Ponziani ◽

Giulia Di Vittorio ◽

Giuseppina Pitari ◽

Anna Maria Cimini ◽

Matteo Ardini ◽

...

Keyword(s):

First Generation ◽

Antitumor Agents ◽

Therapeutic Index ◽

European Medicines Agency ◽

Antibody Drug Conjugates ◽

Drug Conjugates ◽

Recent Developments ◽

Random Coupling ◽

Personalized Cancer ◽

Antibody Drug

In recent years, antibody-drug conjugates (ADCs) have become promising antitumor agents to be used as one of the tools in personalized cancer medicine. ADCs are comprised of a drug with cytotoxic activity cross-linked to a monoclonal antibody, targeting antigens expressed at higher levels on tumor cells than on normal cells. By providing a selective targeting mechanism for cytotoxic drugs, ADCs improve the therapeutic index in clinical practice. In this review, the chemistry of ADC linker conjugation together with strategies adopted to improve antibody tolerability (by reducing antigenicity) are examined, with particular attention to ADCs approved by the regulatory agencies (the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA)) for treating cancer patients. Recent developments in engineering Immunoglobulin (Ig) genes and antibody humanization have greatly reduced some of the problems of the first generation of ADCs, beset by problems, such as random coupling of the payload and immunogenicity of the antibody. ADC development and clinical use is a fast, evolving area, and will likely prove an important modality for the treatment of cancer in the near future.

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A Novel Targeted Approach to Achieve Immune System Reset: CD45-Targeted Antibody Drug Conjugates Enable Autologous HSCT and Ameliorate Disease in Preclinical Autoimmune Disease Models

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2019.12.407 ◽

2020 ◽

Vol 26 (3) ◽

pp. S307-S308

Author(s):

Geoffrey O. Gillard ◽

Jennifer L. Proctor ◽

Melissa L. Brooks ◽

Tahirih L. Lamothe ◽

Sharon L. Hyzy ◽

...

Keyword(s):

Immune System ◽

Autoimmune Disease ◽

Disease Models ◽

Antibody Drug Conjugates ◽

Drug Conjugates ◽

Targeted Approach ◽

Autologous Hsct ◽

Antibody Drug

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Advances and Limitations of Antibody Drug Conjugates for Cancer

Biomedicines ◽

10.3390/biomedicines9080872 ◽

2021 ◽

Vol 9 (8) ◽

pp. 872

Author(s):

Candice Maria Mckertish ◽

Veysel Kayser

Keyword(s):

Therapeutic Index ◽

Narrow Therapeutic Index ◽

Antibody Drug Conjugates ◽

Drug Conjugates ◽

The Stability ◽

Drug Antibody Ratio ◽

Chemotherapy Agents ◽

The Impact ◽

Antibody Ratio ◽

Antibody Drug

The popularity of antibody drug conjugates (ADCs) has increased in recent years, mainly due to their unrivalled efficacy and specificity over chemotherapy agents. The success of the ADC is partly based on the stability and successful cleavage of selective linkers for the delivery of the payload. The current research focuses on overcoming intrinsic shortcomings that impact the successful development of ADCs. This review summarizes marketed and recently approved ADCs, compares the features of various linker designs and payloads commonly used for ADC conjugation, and outlines cancer specific ADCs that are currently in late-stage clinical trials for the treatment of cancer. In addition, it addresses the issues surrounding drug resistance and strategies to overcome resistance, the impact of a narrow therapeutic index on treatment outcomes, the impact of drug–antibody ratio (DAR) and hydrophobicity on ADC clearance and protein aggregation.

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