Single-Chain Fragment Variable: Recent Progress in Cancer Diagnosis and Therapy

Muñoz-López, Paola; Ribas‐Aparicio, Rosa María; Becerra-Báez, Elayne Irene; Fraga-Pérez, Karla; Flores-Martínez, Luis Fernando; Mateos-Chávez, Armando Alfredo; Lurı́a-Pérez, Rosendo

doi:10.3390/cancers14174206

Cited by 42 publications

(17 citation statements)

References 170 publications

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“…The in vivo studies demonstrated that even if T-DM1 has more drug molecules conjugated to the antibody (approximately 3-fold), both of ADCs exhibited very similar in vivo e cacy. This observation correlates with the previous studies, demonstrating that unlike in vitro cell cytotoxicity the higher DAR does not improve therapeutic activity format is less stable and had a tendency to form aggregates because of the lack of FC domain and the small size decrease their half-life under 1 day versus 3 weeks for full length antibodies 31 . Even if CovIsoLink technology succeed to cross links DM-1 successfully with a high e cacy, the physicochemical properties of scfv con rms the low e cacy as scfv ADC.…”

Section: Discussionsupporting

confidence: 91%

Antibody and antibody fragments Site Specific Conjugation using New Q-tag Substrate of Bacterial Transglutaminase.

Alaoui,

Sivado,

Alaoui

et al. 2023

Preprint

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During the last few years Antibody Drug Conjugates (ADCs) have become one of the most active and very promising therapeutic weapons. Lessons learned from the traditional chemical conjugations (via lysine or cysteine residues of the antibodies) and the clinical studies of the developed ADCs have recently paved the way to the improvement of the conjugation technologies. Use of site-specific conjugation is considered as the promising path for improving the design and development of homogeneous ADCs with controlled Drug-Antibody ratio (DAR). Moreover, some of these conjugations can be applied to antibody fragments such as Fab, scfv and VHH for which random and chemical conjugation showed significant limitations. In this study, we identified a novel small peptide substrate (Q-tag) with high affinity and specificity of bacterial transglutaminase which can be genetically fused to different formats of antibodies of interest for the development of enzymatic site-specific conjugation we named “CovIsolink” platform. We describe the synthesis of chemically defined drugs conjugation in which the site and stoichiometry of conjugation are controlled using a genetically encoded Q-tag peptide with specific amino acids which serves as a substrate of bacterial transglutaminase. This approach has enabled the generation of homogeneous conjugates with DAR 1,7 for full IgG and 0,8 drug ratio for Fab, scfv and VHH antibody fragments without the presence of significant amounts of unconjugated antibody and fragments. As a proof of concept, Q-tagged anti Her-2 (human IgG1 (Trastuzumab) and the corresponding fragments (Fab, scfv and VHH) were engineered and conjugated with different aminated-payloads. The corresponding Cov-ADCs were evaluated in series of in vitro and in vivo assays, demonstrating similar tumor cell killing potency as Trastuzumab emtansine (Kadcyla®) even with lower drug-to-antibody ratio (DAR).

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Section: Discussionsupporting

confidence: 91%

Antibody and antibody fragments Site Specific Conjugation using New Q-tag Substrate of Bacterial Transglutaminase.

Alaoui,

Sivado,

Alaoui

et al. 2023

Preprint

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“…The scFv comprises heavy- and light-chain variable region of antibody connected by a short linker peptide consisting of 15–20 amino acids [ 27 ]. Due to their small size, scFvs can penetrate tumors more efficiently than mAbs for solid tumors [ 20 ].…”

Section: Based On Antibody Fragmentsmentioning

confidence: 99%

Reforming solid tumor treatment: the emerging potential of smaller format antibody-drug conjugate

Ma,

Wang,

Ying

et al. 2024

Antibody Therapeutics

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In recent years, substantial therapeutic efficacy of antibody-drug conjugates (ADCs) has been validated through approvals of 16 ADCs for the treatment of malignant tumors. However, realization of the maximum clinical use of ADCs requires surmounting extant challenges, mainly the limitations in tumor penetration capabilities when targeting solid tumors. To resolve the hurdle of suboptimal tumor penetration, miniaturized antibody fragments with engineered formats have been harnessed for ADC assembly. By virtue of their reduced molecular sizes, antibody fragment-drug conjugates (FDCs) hold considerable promise for efficacious delivery of cytotoxic agents, thus conferring superior therapeutic outcomes. This review will focus on current advancements in novel ADC development utilizing smaller antibody formats from approximately 6 to 80 kDa, with particular emphasis on single-domain antibodies, which have been widely applied in novel ADC design. Additionally, strategies to optimize clinical translation are discussed, including half-life extension, acceleration of internalization, and reduction of immunogenic potential.

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“…This structure can retain the antibody's antigen-binding specificity, but it will often reduce its affinity and solubility. Due to the emergence of recombinant DNA technology many antibody domains and fragments have been developed as attractive alternatives to conventional antibodies [ [9] , [10] , [11] , [12] , [13] , [14] ]. Due to their small size, superior properties and ease of manufacturing they became excellent candidates for the development of antibodies against COVID-19.…”

Section: Introductionmentioning

confidence: 99%