Pyridazinediones deliver potent, stable, targeted and efficacious antibody–drug conjugates (ADCs) with a controlled loading of 4 drugs per antibody

Robinson, Eric; Nunes, João P. M.; Vassileva, Vessela; Maruani, Antoine; Nogueira, João C. F.; Smith, Mark E.; Pedley, R. Barbara; Caddick, Stephen; Baker, James R.; Chudasama, Vijay

doi:10.1039/c7ra00788d

Cited by 67 publications

(79 citation statements)

References 46 publications

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“…All five synthesised PDs 2-6 were incubated with human serum albumin (HSA), the blood's most abundant thiol, at pH 7.4 for 4 h, to determine if there was any reactivity with the protein's accessible cysteine residue. Gratifyingly, no reaction was observed between HSA and all of the trialled PDs, corroborating previously reported results that alkyl thio-PDs are stable in blood-mimicking conditions 29 and unveiling aryl thio-PDs to also be stable in the time-frame of the experiment. As a positive control, maleimide was incubated with HSA alongside PDs 2-6 under identical conditions.…”

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confidence: 90%

Fine-tuning thio-pyridazinediones as SMDC scaffolds (with intracellular thiol release via a novel self-immolative linker)

2020

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supporting

confidence: 90%

Fine-tuning thio-pyridazinediones as SMDC scaffolds (with intracellular thiol release via a novel self-immolative linker)

2020

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“…A similar class of molecules called bromopyridazinediones exploit the same principles as substituted maleimides, but pose a hydrolytically stable alternative for cysteine functionalisation [34]. Furthermore, the conjugated pyridazinedione scaffold is stable in vivo (blood) with no further hydrolysis required (Scheme 3b) [35,36]. It is noted however, that this moiety is less reactive towards cysteine than the maleimide scaffold, and so quantitative formation of the bioconjugate can take longer (up to 16 h).…”

Section: Alternative Solutions To Retro-michael Deconjugationmentioning

confidence: 99%

Minireview: Addressing the retro-Michael instability of maleimide bioconjugates

Szijj

Bahou

Chudasama

2018

Drug Discovery Today: Technologies

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“…[20][21][22] Highly homogenous ADCs with a DAR of two or four have been obtained via this strategy, and these show no decrease in antigen-binding and no decrease in circulation half-life. [23][24][25] However, it has been observed that these disulfide residues can re-bridge in a non-native fashion, resulting in the "half-antibody" species 7, thus yielding a mixture of two antibody conjugates ( Figure 1c). 26,27a,27b Currently there have been no studies to suggest this "half-antibody" species (7) negatively affects the profile of the antibody.…”

Section: Introductionmentioning

confidence: 99%

Disulfide Modified IgG1: An Investigation of Biophysical Profile and Clinically Relevant Fc Interactions

et al. 2019

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Modification of immunoglobulin G (IgG) 1 proteins in cancer treatment is a rapidly growing field of research. Antibody-drug conjugates (ADCs) exploit the targeted nature of this immunotherapy by conjugating highly potent drugs to antibodies, allowing for effective transport of cargo(s) to cancerous cells. Of the many bioconjugation strategies now available for the formation of highly homogenous ADCs, disulfide modification is considered an effective, low-cost and widely accepted method for modifying IgG1s for improved clinical benefit. However, little is known about how disulfide modification impacts clinically relevant fragment crystallisable (Fc) region interactions. Although often overlooked as a secondary ADC function, Fc interactions could prove key in rational design of cancer cell-targeting ADCs through consideration of potent mechanisms such as antibodydependant cellular cytotoxicity (ADCC). This work explores different IgG1 disulfide modification techniques and the effect they have on quantifiable secondary IgG1 Fc interactions (e.g. CD16a and FcRn). The solvent accessible disulfide residues of trastuzumab, a clinically relevant IgG1, were modified to provide a range of bioconjugates with differing amounts of inter-chain covalent linkages. It was found that by natively re-bridging the IgG1 model, all tested Fc functionalities were not significantly affected. Additionally, in non Fc-specific biophysical experiments (e.g. thermal stability/aggregation), the natively re-bridged species provided an exceptional profile, showing no significant change from the tested native antibody. Conjugates with significant disruption of the covalent connectivity of IgG1 chains resulted in a suboptimal Fc profile (CD16a kinetics or ADCC activity), in addition to sub-standard non Fc-specific attributes (thermal stability). These results advocate native disulfide re-bridging as an excellent synthetic strategy for forming homogenous IgG1 bioconjugates, with no reported negative impact on biophysical profile relative to the native antibody.

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Pyridazinediones deliver potent, stable, targeted and efficacious antibody–drug conjugates (ADCs) with a controlled loading of 4 drugs per antibody

Abstract: Delivering potent, stable, targeted and in vivo efficacious antibody–drug conjugates (ADCs) using pyridazinedione functional disulfide re-bridging reagents.

Cited by 67 publications

References 46 publications

Fine-tuning thio-pyridazinediones as SMDC scaffolds (with intracellular thiol release via a novel self-immolative linker)

Fine-tuning thio-pyridazinediones as SMDC scaffolds (with intracellular thiol release via a novel self-immolative linker)

Minireview: Addressing the retro-Michael instability of maleimide bioconjugates

Disulfide Modified IgG1: An Investigation of Biophysical Profile and Clinically Relevant Fc Interactions

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