Exo-Linker: Positional Reconfiguration Driving Significant Advances in ADC Stability and Efficacy DOI Open Access

Tomohiro Watanabe,

Tomohiro Fujii,

Yutaka Matsuda

et al.

ADC Review / Journal of Antibody-drug Conjugates, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 30, 2024

Antibody-drug conjugates (ADCs) have transformed targeted cancer therapy by combining the specificity of monoclonal antibodies with cytotoxic potency small-molecule drugs. However, payload instability, hydrophobicity, and premature cleavage limit their efficacy safety. This study presents Exo-Linker technology as a novel solution to these issues. By repositioning cleavable peptide linkers like Glu-Val-Cit Glu-Glu-Val-Cit at exo-position p-aminobenzyl carbamate moiety, Exo-Linkers improve stability, hydrophilicity, resistance enzymatic degradation. Key findings highlight superior pharmacokinetics, tumor-suppressive efficacy, stability ADCs in preclinical models, significantly outperforming traditional Val-Cit-based linkers. Integration second-generation AJICAP platform broadens therapeutic windows, ensures precise drug-to-antibody ratio control, minimizes aggregation. establish new standard for ADC development, overcoming critical limitations while enabling safer more effective treatments. innovative approach redefines landscape, enhances patient outcomes, scope applications.

Language: Английский

Exo-Cleavable Linkers: Enhanced Stability and Therapeutic Efficacy in Antibody–Drug Conjugates DOI Creative Commons

Tomohiro Watanabe,

Naoko Arashida,

Tomohiro Fujii

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(20), P. 18124 - 18138

Published: Oct. 16, 2024

Antibody–drug conjugates (ADCs) combine cytotoxic payloads with monoclonal antibodies through chemical linkers. Finding linkers that both enhance circulatory stability and enable effective tumor payload release remains a challenge. The conventional valine-citrulline (Val-Cit) linker is associated several inherent drawbacks, including hydrophobicity-induced aggregation, limited drug–antibody ratio (DAR), premature release. This study introduces an exolinker approach, repositioning the cleavable peptide at exo position of p-aminobenzylcarbamate moiety, as advancement over linear design, which incorporates hydrophilic glutamic acid, addresses limitations Val-Cit platform improves ADC in vivo profiles. In vitro evaluations showed ADCs reduced release, increased drug-to-antibody ratios, avoided significant even hydrophobic payloads. Furthermore, remained stably attached to presence enzymes like carboxylesterases human neutrophil elastase, indicating potential for favorable safety profile.

Language: Английский

Citations

9
Single-Domain Antibodies as Antibody–Drug Conjugates: From Promise to Practice—A Systematic Review DOI Open Access
Víctor Manuel Medina Pérez, Marta Baselga, Alberto J. Schuhmacher

et al.

Cancers, Journal Year: 2024, Volume and Issue: 16(15), P. 2681 - 2681

Published: July 27, 2024

Background: Antibody–drug conjugates (ADCs) represent potent cancer therapies that deliver highly toxic drugs to tumor cells precisely, thus allowing for targeted treatment and significantly reducing off-target effects. Despite their effectiveness, ADCs can face limitations due acquired resistance potential side Objectives: This study focuses on advances in various ADC components improve both the efficacy safety of these agents, includes analysis several novel formats. work assesses whether unique features VHHs—such as small size, enhanced tissue penetration, stability, cost-effectiveness—make them a viable alternative conventional antibodies reviews current status development. Methods: Following PRISMA guidelines, this focused VHHs ADCs, examining advancements prospects from 1 January 2014 30 June 2024. Searches were conducted PubMed, Cochrane Library, ScienceDirect LILACS using specific terms related single-domain antibodies. Retrieved articles rigorously evaluated, excluding duplicates non-qualifying studies. The selected peer-reviewed analyzed quality synthesized highlight advancements, methods, payloads, future directions research. Results: offer significant advantages drug conjugation over smaller size structure, which enhance penetration enable access previously inaccessible epitopes. Their superior solubility, manufacturability facilitate cost-effective production expand range targetable antigens. Additionally, some naturally cross blood–brain barrier or be easily modified favor making promising targeting brain tumors metastases. Although no VHH–drug (nADC nanoADC) are currently clinical arena, preclinical studies have explored methods linkers. Conclusions: While transforming treatment, mechanisms associated toxicities challenge traditional views bioavailability vary with different types. Severe toxicities, often linked compound instability, effects, nonspecific blood cell interactions, need better understanding. Conversely, rapid distribution, clearance could advantageous, potentially toxicity by minimizing prolonged exposure. These attributes make strong candidates next generation enhancing safety.

Language: Английский

Citations

4
Structural Insights into Lipoate Ligase A-Mediated Antibody Modifications DOI
Kazutoshi Takahashi, Shunsuke Yamazaki, Yutaka Matsuda

et al.

Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 20, 2025

Enzyme-mediated site-specific protein modification is gaining attention in biopharmaceuticals due to its high specificity and mild conditions. Lipoic acid ligase A (LplA) has been widely studied for conjugating short-chain fatty acids lysine residues, traditionally using LAP tags. Recent advances have enabled tag-free LplA modifications, expanding applications antibody-drug conjugates (ADCs) beyond. This study investigates the selective of Lys188 trastuzumab by LplA. Spatial analysis molecular modeling suggest that D151 H189 facilitate nucleophilic attack stabilize intermediates via electrostatic π-cation interactions. These insights enhance our understanding enzyme-driven site selectivity, guiding rational design antibody modifications. The findings support broader ADC production, diagnostics, next-generation biopharmaceuticals, emphasizing role local amino environments enzymatic

Language: Английский

Citations

0
Current advances in separation chemistry for antibody purification and analysis DOI Open Access

Suprit Deol,

Yutaka Matsuda, Yuki Hiruta

et al.

Analytical Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: March 24, 2025

Language: Английский

Citations

0
Exo-Cleavable Linkers: Enhancing Stability and Therapeutic Efficacy in Antibody-Drug Conjugates DOI Creative Commons

Tomohiro Watanabe,

Tomohiro Fujii,

Yutaka Matsuda

et al.

Journal of Synthetic Organic Chemistry Japan, Journal Year: 2024, Volume and Issue: 82(11), P. 1117 - 1124

Published: Nov. 1, 2024

Customized drug delivery systems are essential for precision medicine, with antibody-drug conjugates (ADCs) representing a pivotal approach that integrates cytotoxic payloads monoclonal antibodies (mAbs) through sophisticated chemical linkers. However, optimizing ADC stability while achieving controlled payload release remains challenging. The FDA-approved valine-citrulline (Val-Cit) linker commonly used in ADCs, suffers from issues such as hydrophobicity-induced aggregation, limited drug-antibody ratio (DAR), and premature release.

Language: Английский

Citations

2
Implementing an Efficient Technology Transfer for Biomolecule Production: A Case Study on Continuous-Mode Processes DOI
Yuichi Nakahara, Yuta Endo, Monica Leung

et al.

Organic Process Research & Development, Journal Year: 2024, Volume and Issue: 28(11), P. 3950 - 3958

Published: Aug. 2, 2024

The landscape of biopharmaceutical manufacturing has evolved significantly since 1982, moving from scaling up processes to focusing on quality by design initiatives for ensuring product and consistency. A pivotal aspect this evolution is the technology transfer (TT), a complex, multifaceted process integral rapid production distribution life-saving drugs. This manuscript presents novel approach overcoming one key challenges in TT: replicating conditions across different sites. Our research group developed suitcase-sized portable flow microreactor (FMR), whose optimized includes feedback mechanism based versus pressure or viscosity measurements. innovation simplifies replication conditions, thereby reducing duration complexity TT. We detail successful application strategy case study where interleukin-6 refolding were transferred site Japan United States using FMR. paper not only discusses technological advancements FMR but also explores its implications future transfers industry, emphasizing potential enhance efficiency streamline operations sector time accuracy are paramount.

Language: Английский

Citations

1
Antibody Modification via Lipoic Acid Ligase A‐Mediated Site‐Specific Labeling DOI
Shunsuke Yamazaki, Yutaka Matsuda

Chemistry & Biodiversity, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 22, 2024

Abstract Enzymatic modification, particularly utilizing lipoic acid ligase (LplA), has emerged as a transformative approach in biopharmaceuticals, enabling precise and site‐specific protein modifications. This review delves into the innovative applications of LplA antibody modifications, including creation antibody‐drug conjugates (ADCs) advancement tag‐free conjugation techniques. LplA's ability to facilitate incorporation bioorthogonal groups its adaptability various substrates underscores versatility. Key developments include successful generation dual‐labeled antibodies application modifying fragments. Additionally, explores potential for enhance therapeutic efficacy ADCs through improved drug‐to‐antibody ratios payload attachment. The implications these advancements are significant, suggesting that LplA‐mediated modifications could lead more effective targeted antibody‐based therapies. aims provide comprehensive overview role expanding possibilities enzymatic conjugation, setting stage future research clinical applications.

Language: Английский

Citations

1
Antibody–Drug Conjugates: A Start of a New Era in Gynecological Cancers DOI Creative Commons

Samir Fasih,

Stephen Welch, Ana Elisa Lohmann

et al.

Current Oncology, Journal Year: 2024, Volume and Issue: 31(11), P. 7088 - 7106

Published: Nov. 13, 2024

Antibody-drug conjugates (ADCs) are a new class of therapeutic agents designed to target specific antigens on tumor cells, combining the specificity monoclonal antibodies with cytotoxicity chemotherapy agents. ADCs have been available for over decade, but in gynecological cancers, these relatively great promise ahead. More than 80% ongoing trials cancers evaluating ADCs' safety and efficacy, which 40% early-phase trials. Around twenty currently under investigation, either alone or combination chemotherapies immune checkpoint inhibitors. Among them, mirvetuximab soravtansine has recently approved by Food Drug Administration (FDA) platinum-resistant ovarian cancer high folate-α receptor expression, as single agent combination. Tisotumab vedotin trastuzumab deruxtecan also now FDA patients pre-treated cervical uterine further investigation is ongoing. Overall, toxicity profiles acceptable. Ocular one side effects some ADCs, most cases manageable use prophylactic steroids dose adjustments. This review aims provide an overview fundamental operational features examine latest promising data, particular focus Canadian viewpoint.

Language: Английский

Citations

1
Chemistry of Antibody-Small Molecule Drug Conjugates DOI
Christopher C. Marvin,

Milan Bruncko,

Ippei Usui

et al.

Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Language: Английский

Citations

0
Immunoconjugates as an Efficient Platform for Drug Delivery: A Resurgence of Natural Products in Targeted Antitumor Therapy DOI Creative Commons
Rositsa Mihaylova, Denitsa Momekova,

Viktoria Elincheva

et al.

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(12), P. 1701 - 1701

Published: Dec. 17, 2024

The present review provides a detailed and comprehensive discussion on antibody–drug conjugates (ADCs) as an evolving new modality in the current therapeutic landscape of malignant diseases. principle concepts targeted delivery highly toxic agents forsaken stand-alone drugs are examined detail, along with biochemical technological tools for their successful implementation. An extensive analysis ADCs’ major components is conducted parallel function impact stability, efficacy, safety, resistance profiles immunoconjugates. scope article covers classes currently validated natural compounds used payloads, emphasis structural mechanistic features, origin, distribution. Future perspectives design thoroughly explored, addressing inherent or emerging challenges limitations. survey also overview molecular rationale active tumor targeting ADC-based platforms, exploring cellular biology clinical relevance markers “homing” mechanism both hematological solid malignancies.

Language: Английский

Citations

0