Construction of homogeneous antibody–drug conjugates using site-selective protein chemistry

Akkapeddi, Padma; Azizi, Saara-Anne; Freedy, Allyson M.; Cal, Pedro M. S. D.; Góis, Pedro M. P.; Bernardes, Gonçalo J. L.

doi:10.1039/c6sc00170j

Cited by 140 publications

(127 citation statements)

References 98 publications

(100 reference statements)

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“…[40,107] Although there are already two US Food and Drug Administration-approved ADCs already available on the market and over 30 ADCs [43] in clinical trials, addressing antibody modification while maintaining structural integrity and product homogeneity for precise formulation remains challenging. [108,109] Conventionally, this has been achieved by conjugation strategies that have poor site-selectivity, [110] resulting in heterogeneous mixtures with different drug loadings. The bissulfones, DSMs and dibromopyridazinediones are suitable candidates for the preparation of well-defined ADCs through modification of the accessible disulfides in the hinge region, [43,46,54,55,63] without the need to engineer unnatural amino acids or cysteine mutants.…”

Section: Antibody Biohybridsmentioning

confidence: 99%

Site‐Selective Disulfide Modification of Proteins: Expanding Diversity beyond the Proteome

Kuan

Wang

Weil

2016

Chemistry A European J

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The synthetic transformation of polypeptides with molecular accuracy holds great promise for providing functional and structural diversity beyond the proteome. Consequently, the last decade has seen an exponential growth of site‐directed chemistry to install additional features into peptides and proteins even inside living cells. The disulfide rebridging strategy has emerged as a powerful tool for site‐selective modifications since most proteins contain disulfide bonds. In this Review, we present the chemical design, advantages and limitations of the disulfide rebridging reagents, while summarizing their relevance for synthetic customization of functional protein bioconjugates, as well as the resultant impact and advancement for biomedical applications.

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Section: Antibody Biohybridsmentioning

confidence: 99%

Site‐Selective Disulfide Modification of Proteins: Expanding Diversity beyond the Proteome

Kuan

Wang

Weil

2016

Chemistry A European J

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“…It is the preferred method for the formation of antibody‐drug conjugates . Yet, only few studies are dedicated to the construction of homogeneous bioconjugates which do not exist as mixtures of diastereomers at the ligation site . Our study identifies the stereodynamic and conformational properties of pairs of diastereomeric macrocyclic pentapeptides containing a succinimide thioether where the ring closure is achieved by a thiol 1,4‐addition reaction.…”

Section: Introductionmentioning

confidence: 99%

The stereodynamics of macrocyclic succinimide‐thioethers

Lenz

Horx

Geyer

2018

Journal of Peptide Science

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Maleimide-thiol coupling is a popular bioconjugation strategy, but little is known about the stereoselectivity and the stereodynamics of the succinimide thioether formed in a biopolymer environment. We used thiol 1,4-addition for the macrocyclisation of 5 designed pentapeptides with the ringsize of hexapeptides because they incorporate the succinimide thioether (4-8). Both succinimide diastereomers are observed in the constrained macrocyclic rings in each case. In spite of the low diastereoselectivity of the macrocyclisation reaction, there is a significant influence of the amino acid environment on the epimerization rate of the succinimide. Its half life can be as short as several hours at room temperature when Gly is the amino acid following the succinimide (peptide 8). On the contrary, no epimerization is detectable even after several weeks in the case of d-Phe C-terminal to the succinimide in peptide 4. Already the small selection of examples shows how big the differences in epimerization rates can be and that the local environment has a significant influence. The variation of amino acids in the vicinity of the ligation site points the way towards the synthesis of bioconjugates which are obtained as stable and separable diastereomers.

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“…[27] Therefore, there is no surprise that they have been intensively studied as carriers for drugs and contrast agentsf or cancer therapy and imaging in the last few years. [28,29] However,t he outcome of these efforts is ratherm odest.I tw as suggestedt hat the therapeutic index and safety of antibody-drug conjugates (ADCs) can still be significantly improved by using modern site-selective methods of protein modificationst oc reate nextgeneration ADCs with ad efined drug:antibody ratio (DAR) at specific sites. [30] In this study,w eu sed an engineered trastuzumab presenting an additional free cysteine per light chain-ThiomabL C-V205C (Genentech, Inc.).…”

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confidence: 99%

Synthesis and Biological Evaluation of Homogeneous Thiol‐Linked NHC*‐Au‐Albumin and ‐Trastuzumab Bioconjugates

Matos

Labão-Almeida

Sayers

et al. 2018

Chemistry A European J

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Targeted delivery of potent cytotoxic drugs to cancer cells minimizes systemic toxicity and several side effects. NHC*−Au−Cl has already been proven to be a potent anticancer agent. In this study, we explore a strategy based on chemoselective cysteine conjugation of NHC*−Au−Cl to albumin and trastuzumab (Thiomab LC‐V205C) to potentiate drug‐ligand ratio, pharmacokinetics, as well as drug efficacy and safety. This strategy is a step forward towards the use of gold‐based anticancer agents as targeted therapies.

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Construction of homogeneous antibody–drug conjugates using site-selective protein chemistry

Abstract: The use of site-selective chemical drug-conjugation strategies enables the construction of antibody–drug conjugates (ADCs) with superior therapeutic efficacy.”

Cited by 140 publications

References 98 publications

Site‐Selective Disulfide Modification of Proteins: Expanding Diversity beyond the Proteome

Site‐Selective Disulfide Modification of Proteins: Expanding Diversity beyond the Proteome

The stereodynamics of macrocyclic succinimide‐thioethers

Synthesis and Biological Evaluation of Homogeneous Thiol‐Linked NHC*‐Au‐Albumin and ‐Trastuzumab Bioconjugates

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