Picking the Optimal Target for Antibody-Drug Conjugates

Mathur, Rohan; Weiner, George J.

doi:10.1200/edbook_am.2013.33.e103

Cited by 18 publications

(12 citation statements)

References 27 publications

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“…ADCs combine the cytotoxic potential of drugs with the specificity of mAbs, and theoretically can overcome the limitations of both nonspecific cytotoxic drugs and specific but often ineffective mAbs. The choice of the target antigen and selection of the mAb for ideal ADCs have some characteristics that are different from those used for unlabeled mAbs 89 . Tumor antigens for ADCs can be expressed at lower concentrations when compared to unlabeled mAbs because delivery of a highly toxic drug by a small number of ADC molecules can result in death of the target cancer cell.…”

Section: [H1]delivering Cytotoxic Moietiesmentioning

confidence: 99%

Building better monoclonal antibody-based therapeutics

2015

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For 20 years, monoclonal antibodies (mAbs) have been a standard component of cancer therapy, yet there is still much room for improvement. Efforts continue to build better cancer therapeutics based on mAbs. Anti-cancer mAbs function via a variety of mechanisms including directly targeting the malignant cells, modifying the host response to the malignant cells, delivering cytotoxic moieties to the malignant cells or retargeting cellular immunity towards the malignant cells. Characteristics of mAbs that affect their efficacy include antigen specificity, overall structure, affinity for the target antigen and how a mAb component is incorporated into a construct that can trigger target cell death. This article reviews the various approaches to using mAb-based therapeutics to treat cancer, the strategies used to take advantage of the unique potential of each approach, and provides examples of current mAb-based treatments.

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Section: [H1]delivering Cytotoxic Moietiesmentioning

confidence: 99%

Building better monoclonal antibody-based therapeutics

2015

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“…Critical target-related properties are (a) expression profile, and density (receptor copy number), (b) target internalization and turnover rate, and (c) functional relevance to human disease (18)(19)(20). An ideal target should demonstrate a specific expression profile at the relevant site of action (typically tumor cells) with little to no expression in other healthy tissues (18,19). Target expression and density should also be in sufficient concentrations to facilitate delivery of a potent payload into the effect compartment ("Impact of Target Density and Internalization Rate on Payload Delivery" section).…”

Section: Considerations For Target Selection and Modality Designmentioning

confidence: 99%

“…Target expression and density should also be in sufficient concentrations to facilitate delivery of a potent payload into the effect compartment ("Impact of Target Density and Internalization Rate on Payload Delivery" section). In most instances, application of ADCs would necessitate an internalization step in order to facilitate intracellular uptake and payload release (18,19). Rate of internalization or target turnover rate is a critical parameter that controls the efficiency of the payload delivery into the biophase ("Impact of Target Density and Internalization Rate on Payload Delivery" section).…”

Section: Considerations For Target Selection and Modality Designmentioning

confidence: 99%

Antibody Drug Conjugates: Application of Quantitative Pharmacology in Modality Design and Target Selection

Sadekar

Figueroa²,

Tabrizi³

2015

AAPS J

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Abstract. Antibody drug conjugates (ADCs) are a multi-component modality comprising of an antibody targeting a cell-specific antigen, a potent drug/payload, and a linker that can be processed within cellular compartments to release payload upon internalization. Numerous ADCs are being evaluated in both research and clinical settings within the academic and pharmaceutical industry due to their ability to selectively deliver potent payloads. Hence, there is a clear need to incorporate quantitative approaches during early stages of drug development for effective modality design and target selection. In this review, we describe a quantitative approach and framework for evaluation of the interplay between drug-and systems-dependent properties (i.e., target expression, density, localization, turnover, and affinity) in order to deliver a sufficient amount of a potent payload into the relevant target cells. As discussed, theoretical approaches with particular considerations given to various key properties for the target and modality suggest that delivery of the payload into particular effect cells to be more sensitive to antigen concentrations for targets with slow turnover rates as compared to those with faster internalization rates. Further assessments also suggest that increasing doses beyond the threshold of the target capacity (a function of target internalization and expression) may not impact the maximum amount of payload delivered to the intended effect cells. This article will explore the important application of quantitative sciences in selection of the target and design of ADC modalities.

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“…Immunoconjugates include the anti-CD20 radioconjugates 90 Y-ibritumomab tiuxetan and 131 I-tositumomab for lymphoma, and a number of antibody drug conjugates that are showing promise in both hematologic malignancies and solid tumors [12]. While some may not consider immunoconjugates to be “immunotherapy” because the mechanism of tumor cell lysis is not limited to immune-mediated lysis, immunoconjugates do rely on immune recognition of the target antigen and provide an effective approach to overcoming immune tolerance.…”

Section: Introductionmentioning

confidence: 99%

Cancer Immunotherapy and Breaking Immune Tolerance: New Approaches to an Old Challenge

2015

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Cancer immunotherapy has proven to be challenging as it depends on overcoming multiple mechanisms that mediate immune tolerance to self-antigens. A growing understanding of immune tolerance has been the foundation for new approaches to cancer immunotherapy. Adoptive transfer of immune effectors such as antitumor monoclonal antibodies and Chimeric Antigen Receptor T cells bypasses many of the mechanisms involved in immune tolerance by allowing for expansion of tumor specific effectors ex vivo. Vaccination with whole tumor cells, protein, peptide, or dendritic cells has proven challenging, yet may be more useful when combined with other cancer immunotherapeutic strategies. Immunomodulatory approaches to cancer immunotherapy include treatment with agents that enhance and maintain T cell activation. Recent advances in the use of checkpoint blockade to block negative signals and so maintain the antitumor response are particularly exciting. With our growing knowledge of immune tolerance and ways to overcome it, combination treatments are being developed, tested and have particular promise. One example is in situ immunization that is designed to break tolerance within the tumor microenvironment. Progress in all these areas is continuing based on clear evidence that cancer immunotherapy designed to overcome immune tolerance can be useful for a growing number of cancer patients.

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Picking the Optimal Target for Antibody-Drug Conjugates

Cited by 18 publications

References 27 publications

Building better monoclonal antibody-based therapeutics

Building better monoclonal antibody-based therapeutics

Antibody Drug Conjugates: Application of Quantitative Pharmacology in Modality Design and Target Selection

Cancer Immunotherapy and Breaking Immune Tolerance: New Approaches to an Old Challenge

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