Lipoate-acid ligase a modification of native antibody: Synthesis and conjugation site analysis

Yamazaki, Shunsuke; Shikida, Natsuki; Takahashi, Kazutoshi; Matsuda, Yutaka; Inoue, Kota; Shimbo, Kazutaka; Mihara, Yuko

doi:10.1016/j.bmcl.2021.128360

Cited by 22 publications

(41 citation statements)

References 34 publications

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“…This observation may be supported by conjugation site analysis of T-DM1 [ 23 ]. Conjugation site analysis using peptide mapping was reported by several groups [ 23 – 25 ], and solvent exposure analysis to compare T-DM1 and naked trastuzumab indicated that most modification to produce T-DM1 happened in Fab and CH2 domains [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Physical characteristics comparison between maytansinoid-based and auristatin-based antibody-drug conjugates

Fujii

Reiling²,

Quinn

et al. 2021

Exploration of Targeted Anti-Tumor Therapy

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Aim: Direct analytical comparison of two major drug-linkers in the antibody-drug conjugate (ADC) field was conducted. Methods: Four different analytical methods [AlogP calculation, reverse phase (RP) high-performance liquid chromatography (HPLC; RP-HPLC), size exclusion chromatography HPLC (SEC-HPLC), and differential scanning calorimetry (DSC)] were tested for this comparison. Results: Maytansinoid-based ADCs showed less hydrophobicity than auristatin-based ADCs. Regardless of the drug-linker and drug-to-antibody ratios (DARs), the stability detected by DSC was decreased by conjugation. Conclusions: The cost and time-efficient analytical comparison described in this manuscript may be useful information for an initial characterization of ADCs prior to detailed biological studies.

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Section: Discussionmentioning

confidence: 99%

Physical characteristics comparison between maytansinoid-based and auristatin-based antibody-drug conjugates

Fujii

Reiling²,

Quinn

et al. 2021

Exploration of Targeted Anti-Tumor Therapy

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“…At room temperature or higher, the aggregation percentage increased significantly; however, in the current study, trastuzumab-AJICAPmaytansinoid showed more resistance to high temperature than T-DM1. As described above, T-DM1 has a heterogeneous mixture of possibly more than 80 species [27], some of which may be unstable and prone to aggregation. In contrast, AJICAP-ADC is a low heterogeneous ADC; its conjugation position is known to be stable under thermal/blood circulation.…”

Section: Gram-scale Preparation and Analysis Of Trastuzumab-ajicap-ma...mentioning

confidence: 96%

Biological Evaluation of Maytansinoid-Based Site-Specific Antibody-Drug Conjugate Produced by Fully Chemical Conjugation Approach: AJICAP®

Seki¹,

Yamada²,

Ooba³

et al. 2022

Front. Biosci. (Landmark Ed)

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Background: Trastuzumab-emtansine (T-DM1, commercial name: Kadcyla) is well-known antibody-drug conjugate (ADC) and was first approved for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. This molecular format consisting of trastuzumab and maytansinoid payload (emtansine) is very simple, however, T-DM1 has wide heterogeneity due to non-specific conjugation, lowering its therapeutic index (TI). Methods: To overcome this issue during the chemical modification of the random conjugation approach to generate T-DM1, we developed a novel chemical conjugation technology termed "AJICAP®" for modification of antibodies in site-specific manner by IgG Fc-affinity peptide based reagents. Results: In this study, we compared site-specific maytansinoidbased ADCs synthesized by AJICAP and T-DM1 in rat safety studies. The results indicated an increase in the maximum tolerated dose, demonstrating an expansion of the AJICAP-ADC therapeutic index compared with that of commercially available T-DM1. Gram scale preparation of this AJICAP-ADC and the initial stability study are also described. Conclusions: Trastuzumab-AJICAP-maytansinoid produced by this unique chemical conjugation methodology showed higher stability and tolerability than commercially available T-DM1.

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“…first reported the use of LplA‐mediated antibody modification to synthesize a site‐specific antibody conjugates; however, this process also required the presence of an LplA acceptor peptide tag moiety [84] . Bacterial LplA modification of native mAb under mild conditions was subsequently reported by Yamazaki et al [85] . An intact‐mass spectrometry analysis revealed almost complete conversion of IgG1 to conjugates by LplA.…”

Section: Lipoic Acid Ligase a Modificationmentioning

confidence: 99%

“…One disadvantage of this newly reported approach is the incomplete site‐specificity. However, researchers at Ajinomoto Co., Inc. have indicated that optimizations to enzyme mutation were recently undertaken and this issue may be resolved [85] . Currently, tag‐free enzymatic modification of antibody fragments has been reported only by LplA.…”

Section: Comparison Of Three Enzymatic Conjugation Processesmentioning

confidence: 99%

Tag‐Free Enzymatic Modification for Antibody−Drug Conjugate Production

Yamazaki

Matsuda

2022

ChemistrySelect

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Currently, although >10 antibody−drug conjugates (ADCs) are available in the market, most of them (10 ADCs) have broad drug distribution, thereby potentially limiting their therapeutic index. The ADC industry is shifting from random conjugation technology to site‐specific conjugation technology to overcome this issue. Enzymatic site‐specific conjugation is a promising cutting‐edge technology owing to its mild conjugation conditions. This review discussed enzymatic conjugation strategies for producing ADCs via modifying native antibodies without using a tag moiety. We described the comparison of the three main conjugation technologies used to produce site‐specific ADCs. Each of the three enzymatic approaches described in this review differs in their advantages and disadvantages, providing pharmaceutical companies the option to select an approach suitable to their purpose and/or target protein.

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Lipoate-acid ligase a modification of native antibody: Synthesis and conjugation site analysis

Cited by 22 publications

References 34 publications

Physical characteristics comparison between maytansinoid-based and auristatin-based antibody-drug conjugates

Physical characteristics comparison between maytansinoid-based and auristatin-based antibody-drug conjugates

Biological Evaluation of Maytansinoid-Based Site-Specific Antibody-Drug Conjugate Produced by Fully Chemical Conjugation Approach: AJICAP®

Tag‐Free Enzymatic Modification for Antibody−Drug Conjugate Production

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