The Chemistry Behind ADCs

Kostova, Vesela; Desos, Patrice; Starck, Jérôme-Benoît; Kotschy, András

doi:10.3390/ph14050442

Cited by 73 publications

(78 citation statements)

References 152 publications

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“…While several publications have listed Lumoxiti ® (moxetumomab pasudotox-tdfk) as an FDA approved ADC [ 8 , 9 ], we have excluded it from our discussions as we consider it an immunotoxin [ 10 , 11 , 12 , 13 ]. Besides Lumoxiti ® [ 14 , 15 ], the immunotoxins Ontak ® (denileukin diffittox) [ 16 ] and Elzonris ® (tagraxofusp-erzs) [ 17 ], have also been granted FDA approval.…”

Section: Introductionmentioning

confidence: 99%

“…We recommend several excellent review articles in the field of ADCs for more detail and to promote the understanding and an appreciation of these next-generation therapeutics [19][20][21][22][23][24]. While several publications have listed Lumoxiti ® (moxetumomab pasudotox-tdfk) as an FDA approved ADC [8,9], we have excluded it from our discussions as we consider it an immunotoxin [10][11][12][13]. Besides Lumoxiti ® [14,15], the immunotoxins Ontak ® (denileukin diffittox) [16] and Elzonris ® (tagraxofusp-erzs) [17], have also been granted FDA approval.…”

Section: Introductionmentioning

confidence: 99%

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An Insight into FDA Approved Antibody-Drug Conjugates for Cancer Therapy

et al. 2021

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The large number of emerging antibody-drug conjugates (ADCs) for cancer therapy has resulted in a significant market ‘boom’, garnering worldwide attention. Despite ADCs presenting huge challenges to researchers, particularly regarding the identification of a suitable combination of antibody, linker, and payload, as of September 2021, 11 ADCs have been granted FDA approval, with eight of these approved since 2017 alone. Optimism for this therapeutic approach is clear, despite the COVID-19 pandemic, 2020 was a landmark year for deals and partnerships in the ADC arena, suggesting that there remains significant interest from Big Pharma. Herein we review the enthusiasm for ADCs by focusing on the features of those approved by the FDA, and offer some thoughts as to where the field is headed.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An Insight into FDA Approved Antibody-Drug Conjugates for Cancer Therapy

et al. 2021

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“…Numerous reviews exist that provide excellent general overviews of ADCs for cancer therapy [ 9 , 10 , 14 , 15 , 16 ]. In addition, reviews exist that provide more focused descriptions of linker and conjugation chemistries [ 17 , 18 , 19 , 20 ], current and emerging payloads [ 10 , 21 ], and ADC resistance mechanisms [ 10 , 22 , 23 ]. With respect to the actions of ADCs once internalized, there are enlightening reviews that describe the intracellular trafficking dynamics and their implications for ADC efficacy [ 6 , 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

Impact of Endocytosis Mechanisms for the Receptors Targeted by the Currently Approved Antibody-Drug Conjugates (ADCs)—A Necessity for Future ADC Research and Development

2021

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Biologically-based therapies increasingly rely on the endocytic cycle of internalization and exocytosis of target receptors for cancer therapies. However, receptor trafficking pathways (endosomal sorting (recycling, lysosome localization) and lateral membrane movement) are often dysfunctional in cancer. Antibody-drug conjugates (ADCs) have revitalized the concept of targeted chemotherapy by coupling inhibitory antibodies to cytotoxic payloads. Significant advances in ADC technology and format, and target biology have hastened the FDA approval of nine ADCs (four since 2019). Although the links between aberrant endocytic machinery and cancer are emerging, the impact of dysregulated internalization processes of ADC targets and response rates or resistance have not been well studied. This is despite the reliance on ADC uptake and trafficking to lysosomes for linker cleavage and payload release. In this review, we describe what is known about all the target antigens for the currently approved ADCs. Specifically, internalization efficiency and relevant intracellular sorting activities are described for each receptor under normal processes, and when complexed to an ADC. In addition, we discuss aberrant endocytic processes that have been directly linked to preclinical ADC resistance mechanisms. The implications of endocytosis in regard to therapeutic effectiveness in the clinic are also described. Unexpectedly, information on endocytosis is scarce (absent for two receptors). Moreover, much of what is known about endocytosis is not in the context of receptor-ADC/antibody complexes. This review provides a deeper understanding of the pertinent principles of receptor endocytosis for the currently approved ADCs.

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“…The goal of these molecules is to transport the cytotoxic agent to tumor cells, maximizing efficacy and minimizing toxicity against non-tumoral tissues [ 1 , 2 ]. An ADC is made of three components: (i) the mAb, (ii) a linker, and (iii) the cytotoxic drug ( Figure 1 ) [ 3 ]. The mAb must recognize a tumor-associated antigen.…”

Section: Introduction: Adc Structure and Mechanism Of Actionmentioning

confidence: 99%

Generation of Antibody-Drug Conjugate Resistant Models

Gandullo-Sánchez

Ocaña

Pandiella

2021

Cancers

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In the last 20 years, antibody-drug conjugates (ADCs) have been incorporated into the oncology clinic as treatments for several types of cancer. So far, the Food and Drug Administration (FDA) has approved 11 ADCs and other ADCs are in the late stages of clinical development. Despite the efficacy of this type of drug, the tumors of some patients may result in resistance to ADCs. Due to this, it is essential not only to comprehend resistance mechanisms but also to develop strategies to overcome resistance to ADCs. To reach these goals, the generation and use of preclinical models to study those mechanisms of resistance are critical. Some cells or patient tumors may result in primary resistance to the action of an ADC, even if they express the antigen against which the ADC is directed. Isolated primary tumoral cells, cell lines, or patient explants (patient-derived xenografts) with these characteristics can be used to study primary resistance. The most common method to generate models of secondary resistance is to treat cancer cell lines or tumors with an ADC. Two strategies, either continuous treatment with the ADC or intermittent treatment, have successfully been used to develop those resistance models.

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The Chemistry Behind ADCs

Cited by 73 publications

References 152 publications

An Insight into FDA Approved Antibody-Drug Conjugates for Cancer Therapy

An Insight into FDA Approved Antibody-Drug Conjugates for Cancer Therapy

Impact of Endocytosis Mechanisms for the Receptors Targeted by the Currently Approved Antibody-Drug Conjugates (ADCs)—A Necessity for Future ADC Research and Development

Generation of Antibody-Drug Conjugate Resistant Models

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