Tunable Degradation of Maleimide–Thiol Adducts in Reducing Environments

Baldwin, Aaron D.; Kiick, Kristi L.

doi:10.1021/bc200148v

Cited by 371 publications

(421 citation statements)

References 38 publications

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“…A variety of forms of the ADC may be generated in vivo. For example, variants derived from ADCs, based on maleimide adducts have been described (38)(39)(40). Reactivity of ADA for all three structural components of the ADC (mAb, linker, and small-molecule drug) can be determined.…”

Section: Ada Domain Specificity Strategymentioning

confidence: 99%

Immunogenicity of Antibody Drug Conjugates: Bioanalytical Methods and Monitoring Strategy for a Novel Therapeutic Modality

Hock

Thudium

Carrasco‐Triguero³

et al. 2014

AAPS J

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Abstract. Immunogenicity (the development of an adaptive immune response reactive with a therapeutic) is a well-described but unwanted facet of biotherapeutic development. There are commonly applied procedures for immunogenicity risk assessment, testing strategies, and bioanalysis. With some modifications, these can be applied to new biotherapeutic modalities. For novel therapies such as antibody-drug conjugates (ADCs), the unique structural components may contribute additional complexities to both immunologic responses and bioanalytical methods. US product inserts (USPIs) for two commercially available ADCs detail the incidence of immunogenicity; however, the body of literature on immunogenicity of ADCs is limited. We recently participated in a conference session on this topic (Annual meeting of the American Association of Pharmaceutical Scientists, held November 2013 in San Antonio, TX, USA. The meeting featured the Symposium: Immunogenicity Assessment for Novel Antibody Drug Conjugates, Nonclinical to Clinical) which prompted an effort to share our perspectives on how immunogenicity risk assessment, testing strategies, and bioanalytical methods can be adapted to reflect the complexity of ADC therapeutics.

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Section: Ada Domain Specificity Strategymentioning

confidence: 99%

Immunogenicity of Antibody Drug Conjugates: Bioanalytical Methods and Monitoring Strategy for a Novel Therapeutic Modality

Hock

Thudium

Carrasco‐Triguero³

et al. 2014

AAPS J

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“…Detailed synthetic procedures and characterizations were provided as supplemental material for 2-(2-hydroxyethoxy)ethyl 4-nitrobenze- 19 F-DEG-VS-c(RGDyK), 19 F-DEG-VS-NT, 19 F-DEG-VS-(Ac)-NT, 19 F-FBEM-c(RGDyC), and 19 F-FBEM-NT.…”

Section: Chemistrymentioning

confidence: 99%

“…The in vitro NTR1-binding affinities of 19 F-DEG-VS-NT and NT (8)(9)(10)(11)(12)(13) were assessed via competitive cell-binding assays using 125 I-NT (8-13) (PerkinElmer) as described previously (supplemental material) (22). Small-animal PET imaging was performed in nude mice bearing HT-29 colorectal xenografts after tail vein injection with 3.7 MBq of 18 F-DEG-VS-NT or 18 F-FBEM-NT (n 5 3, respectively).…”

Section: In Vitro Cell-binding Assaymentioning

confidence: 99%

“…Second, 18 F-VS synthon might be obtained through a 1-step 18 F-fluorination, greatly simplifying the synthetic procedure. And third, VS conjugates are stable in aqueous solution for extended periods and are not subject to hydrolysis at neutral pH like maleimide conjugates (15)(16)(17)(18)(19). Thus, VS has an excellent potential for conjugation to thiol-containing peptides or other biomolecules even when used in aqueous buffer conditions.…”

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confidence: 99%

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Facile Preparation of a Thiol-Reactive ¹⁸F-Labeling Agent and Synthesis of ¹⁸F-DEG-VS-NT for PET Imaging of a Neurotensin Receptor–Positive Tumor

Liu

et al. 2014

J Nucl Med

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Accumulating evidence suggests that neurotensin receptors (NTRs) play key roles in cancer growth and survival. In this study, we developed a simple and efficient method to radiolabel neurotensin peptide with 18 F for NTR-targeted imaging. Methods: The thiolreactive reagent 18 F-(2-(2-(2-fluoroethoxy)ethoxy)ethylsulfonyl)ethane ( 18 F-DEG-VS) was facilely prepared through 1-step radiofluorination. After high-pressure liquid chromatography purification, 18 F-DEG-VS was incubated with the c(RGDyC) and c(RGDyK) peptide mixture to evaluate its specificity toward the reactive thiol. Thiolated neurotensin peptide was then labeled with 18 F using this novel synthon, and the resulting imaging probe was subjected to receptor-binding assay and small-animal PET studies in a murine xenograft model. The imaging results and metabolic stability of 18 F-DEG-VS-NT were compared with the thiol-specific maleimide derivative N-[2-(4-18 F-fluorobenzamido) ethyl]maleimide-neurotensin ( 18 F-FBEM-NT). Results: 18 F-DEG-VS was obtained in high labeling yield. The reaction of 19 F-DEG-VS was highly specific for thiols at neutral pH, whereas the lysine of c(RGDyK) reacted at a pH greater than 8.5. 18 F-DEG-VS-c(RGDyC) was the preferred product when both c(RGDyK) and c(RGDyC) were incubated together with 18 F-DEG-VS. Thiolated neurotensin peptide (Cys-NT) efficiently reacted with 18 F-DEG-VS, with a 95% labeling yield (decay-corrected). The radiochemical purity of the 18 F-DEG-VS-NT was greater than 98%, and the specific activity was about 19.2 ± 4.3 TBq/mmol. Noninvasive small-animal PET demonstrated that 18 F-DEG-VS-NT had an NTR-specific tumor uptake in subcutaneous HT-29 xenografts. The tumor-to-muscle, tumor-to-liver, and tumor-to-kidney ratios reached 30.65 ± 22.31, 11.86 ± 1.98, and 1.91 ± 0.43 at 2 h after injection, respectively, based on the biodistribution study. Receptor specificity was demonstrated by blocking experiment. Compared with 18 F-FBEM-NT, 18 F-DEG-VS-NT was synthesized with fewer steps and provided significantly improved imaging quality in vivo. Conclusion: We have established a facile 18 F-labeling method for site-specific labeling of the Cys-NT. Using this method, we synthesized an NTR-targeted PET agent, which demonstrated high tumor-to-background contrast.

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“…However, a recent study has shown that Ab-SMCC-DM1 conjugates are not susceptible to this type of cleavage (24). The superior thioether stability of the Ab-SMCC-DM1 ADCs as compared to the cysteine linked ADCs may stem from inherent differences in the Michael donor reactivity of the sulfhydryl group of DM1 vs. the sulfhydryl group of cysteine side chains (25). Additional work is necessary to understand the mechanism(s) that underlie these pharmacokinetic observations (11,13,21).…”

Section: Pharmacokineticsmentioning

confidence: 99%

ADME of Antibody–Maytansinoid Conjugates

Erickson

Lambert

2012

AAPS J

114

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Abstract. The concept of treating cancer with antibody-drug conjugates (ADCs) has gained momentum with the favorable activity and safety of trastuzumab emtansine (T-DM1), SAR3419, and lorvotuzumab mertansine (IMGN901). All three ADCs utilize maytansinoid cell-killing agents which target tubulin and suppress microtubule dynamics. Each ADC utilizes a different optimized chemical linker to attach the maytansinoid to the antibody. Characterizing the absorption, distribution, metabolism, and excretion (ADME) of these ADCs in preclinical animal models is important to understanding their efficacy and safety profiles. The ADME properties of these ADCs in rodents were inferred from studies with radiolabeled ADCs prepared with nonbinding antibodies since T-DM1, SAR3419, IMGN901 all lack crossreactivity with rodent antigens. For studies exploring tumor localization and activation in tumor-bearing mice, tritium-labeled T-DM1, SAR3419, and IMGN901 were utilized. The chemical nature of the linker was found to have a significant impact on the ADME properties of these ADCs-particularly on the plasma pharmacokinetics and observed catabolites in tumor and liver tissues. Despite these differences, T-DM1, SAR3419, and IMGN901 were all found to facilitate efficient deliveries of active maytansinoid catabolites to the tumor tissue in mouse xenograft models. In addition, all three ADCs were effectively detoxified during hepatobiliary elimination in rodents.

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Tunable Degradation of Maleimide–Thiol Adducts in Reducing Environments

Cited by 371 publications

References 38 publications

Immunogenicity of Antibody Drug Conjugates: Bioanalytical Methods and Monitoring Strategy for a Novel Therapeutic Modality

Immunogenicity of Antibody Drug Conjugates: Bioanalytical Methods and Monitoring Strategy for a Novel Therapeutic Modality

Facile Preparation of a Thiol-Reactive ¹⁸F-Labeling Agent and Synthesis of ¹⁸F-DEG-VS-NT for PET Imaging of a Neurotensin Receptor–Positive Tumor

ADME of Antibody–Maytansinoid Conjugates

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Tunable Degradation of Maleimide–Thiol Adducts in Reducing Environments

Cited by 371 publications

References 38 publications

Immunogenicity of Antibody Drug Conjugates: Bioanalytical Methods and Monitoring Strategy for a Novel Therapeutic Modality

Immunogenicity of Antibody Drug Conjugates: Bioanalytical Methods and Monitoring Strategy for a Novel Therapeutic Modality

Facile Preparation of a Thiol-Reactive 18F-Labeling Agent and Synthesis of 18F-DEG-VS-NT for PET Imaging of a Neurotensin Receptor–Positive Tumor

ADME of Antibody–Maytansinoid Conjugates

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Facile Preparation of a Thiol-Reactive ¹⁸F-Labeling Agent and Synthesis of ¹⁸F-DEG-VS-NT for PET Imaging of a Neurotensin Receptor–Positive Tumor