Non-internalising antibody–drug conjugates

Ashman, Nicola; Bargh, Jonathan D; Spring, David R.

doi:10.1039/d2cs00446a

Cited by 43 publications

(58 citation statements)

References 56 publications

(101 reference statements)

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“…Additionally, non-internalising ADCs directed towards non-cellular components of the tumour microenvironment, such as the neovasculature or extracellular matrix proteins up-regulated during cancer, may be designed using linkers that are specifically cleaved by tumour-specific proteases ( Figure 1 E). These ADCs are designed to potentiate the extracellular release of membrane-permeable cytotoxic payloads specifically at tumour sites [ 24 ]. Examples of non-internalising ADCs evaluated in pre-clinical studies are F16-MMAE and F16-PNU159682, which comprise an IgG1 antibody (F16) targeting the splice variant of tenascin-C, a glycoprotein of the extracellular matrix that is expressed in the stroma of several lymphomas, conjugated via cleavable linkers to MMAE or the anthracycline derivative PNU159682, respectively [ 25 , 26 ].…”

Section: Key Features Of Adcsmentioning

confidence: 99%

Target Antigen Attributes and Their Contributions to Clinically Approved Antibody-Drug Conjugates (ADCs) in Haematopoietic and Solid Cancers

Esapa

Jiang

Cheung

et al. 2023

Cancers

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Antibody drug conjugates (ADCs) are powerful anti-cancer therapies comprising an antibody joined to a cytotoxic payload through a chemical linker. ADCs exploit the specificity of antibodies for their target antigens, combined with the potency of cytotoxic drugs, to selectively kill target antigen-expressing tumour cells. The recent rapid advancement of the ADC field has so far yielded twelve and eight ADCs approved by the US and EU regulatory bodies, respectively. These serve as effective targeted treatments for several haematological and solid tumour types. In the development of an ADC, the judicious choice of an antibody target antigen with high expression on malignant cells but restricted expression on normal tissues and immune cells is considered crucial to achieve selectivity and potency while minimising on-target off-tumour toxicities. Aside from this paradigm, the selection of an antigen for an ADC requires consideration of several factors relating to the expression pattern and biological features of the target antigen. In this review, we discuss the attributes of antigens selected as targets for antibodies used in clinically approved ADCs for the treatment of haematological and solid malignancies. We discuss target expression, functions, and cellular kinetics, and we consider how these factors might contribute to ADC efficacy.

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Section: Key Features Of Adcsmentioning

confidence: 99%

Target Antigen Attributes and Their Contributions to Clinically Approved Antibody-Drug Conjugates (ADCs) in Haematopoietic and Solid Cancers

Esapa

Jiang

Cheung

et al. 2023

Cancers

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“…In the process, we can understand the impact of the complexity added by the microenvironment layers within cells, tissues, animals, and humans. This approach can complement the ongoing efforts to develop covalent regulators and inhibitors. − Besides, controlling selectivity with isolated proteins, enzymes, and antibodies would empower biologics. − The overlap of knowledge between segments at the two ends of the complexity scale, from small molecules to humans, must evolve with time to meet the technological demands.…”

Section: Introductionmentioning

confidence: 99%

Disintegrate (DIN) Theory Enabling Precision Engineering of Proteins

Chauhan

Kumar

et al. 2023

ACS Cent. Sci.

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The chemical toolbox for the selective modification of proteins has witnessed immense interest in the past few years. The rapid growth of biologics and the need for precision therapeutics have fuelled this growth further. However, the broad spectrum of selectivity parameters creates a roadblock to the field's growth. Additionally, bond formation and dissociation are significantly redefined during the translation from small molecules to proteins. Understanding these principles and developing theories to deconvolute the multidimensional attributes could accelerate the area. This outlook presents a disintegrate (DIN) theory for systematically disintegrating the selectivity challenges through reversible chemical reactions. An irreversible step concludes the reaction sequence to render an integrated solution for precise protein bioconjugation. In this perspective, we highlight the key advancements, unsolved challenges, and potential opportunities.

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“…This non-internalising mechanism of action may avoid some of the limitations associated with internalising ADCs such as inefficient internalisation, lack of suitable internalising antigen targets, and acquired resistance related to the internalisation process. 15,16…”

mentioning

confidence: 99%

“…This noninternalising mechanism of action may avoid some of the limitations associated with internalising ADCs such as inefficient internalisation, lack of suitable internalising antigen targets, and acquired resistance related to the internalisation process. 15,16 Programmed cell death ligand-1 (PD-L1) overexpression has been identified in many malignancies and several antibodies which block the PD-L1-PD1 binding interaction have gained FDA approval. Recent work has also investigated the generation of PD-L1 ADCs.…”

mentioning

confidence: 99%

“…Recent work has also investigated the generation of PD-L1 ADCs. 17 Given that some antibodies targeting PD-L1 do not internalise well/quickly, 16 we sought to conjugate peroxide-cleavable linkers with anti-PD-L1 antibody durvalumab to generate a noninternalising ADC. Durvalumab was subjected to the bioconjugation conditions previously employed for trastuzumab (Fig.…”

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confidence: 99%

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