Site-Specific Trastuzumab Maytansinoid Antibody–Drug Conjugates with Improved Therapeutic Activity through Linker and Antibody Engineering

2014 ◽  
Vol 57 (19) ◽  
pp. 7890-7899 ◽  
Author(s):  
Thomas H. Pillow ◽  
Janet Tien ◽  
Kathryn L. Parsons-Reponte ◽  
Sunil Bhakta ◽  
Hao Li ◽  
...  
Keyword(s):  
Antibody Engineering ◽  
Therapeutic Activity ◽  
Site Specific ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

scholarly journals Importance and Considerations of Antibody Engineering in Antibody-Drug Conjugates Development from a Clinical Pharmacologist’s Perspective

Antibodies ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 30
Author(s):  
Andrew T. Lucas ◽  
Amber Moody ◽  
Allison N. Schorzman ◽  
William C. Zamboni
Keyword(s):  
Immune System ◽  
Market Value ◽  
Therapeutic Index ◽  
Drug Carriers ◽  
Antibody Engineering ◽  
Antibody Drug Conjugates ◽  
Success Stories ◽  
Drug Conjugates ◽  
Early Success ◽  
Antibody Drug

Antibody-drug conjugates (ADCs) appear to be in a developmental boom, with five FDA approvals in the last two years and a projected market value of over $4 billion by 2024. Major advancements in the engineering of these novel cytotoxic drug carriers have provided a few early success stories. Although the use of these immunoconjugate agents are still in their infancy, valuable lessons in the engineering of these agents have been learned from both preclinical and clinical failures. It is essential to appreciate how the various mechanisms used to engineer changes in ADCs can alter the complex pharmacology of these agents and allow the ADCs to navigate the modern-day therapeutic challenges within oncology. This review provides a global overview of ADC characteristics which can be engineered to alter the interaction with the immune system, pharmacokinetic and pharmacodynamic profiles, and therapeutic index of ADCs. In addition, this review will highlight some of the engineering approaches being explored in the creation of the next generation of ADCs.

scholarly journals Site-Specific and Trigger-Activated Modification of Proteins by Means of Catalytic Hemin/G-quadruplex (hGQ) DNAzyme Nanostructures

2020 ◽  
Author(s):  
Jordi Keijzer ◽  
Bauke Albada
Keyword(s):  
Heavy Chain ◽  
Protein Modification ◽  
Site Specificity ◽  
Site Specific ◽  
Antibody Drug Conjugates ◽  
Synthetic Dna ◽  
Drug Conjugates ◽  
Sds Page ◽  
G Quadruplex ◽  
Antibody Drug

<div>Synthetic DNA that forms various G-quadruplex nanostructures, in combination with hemin, <i>N</i>-methyl luminol derivatives, and H2O2 can site-specifically modify proteins (i.e. evidence is provided for lysozyme and human alpha-thrombin). The catalytic modification is completed in 15-30 mins, and the site-specificity is influenced by the G-quadruplex topology (a total of 22 G-quadruplex forming sequences was tested). We also show that the heavy chain of the therapeutic antibody trastuzumab is modified, which facilitates the preparation of antibody-drug conjugates. Furthermore, a trigger can be programmed into this synthetic DNA so that the protein modification chemistry is made dependent on an external trigger.</div><div><br></div>Techniques used: HPLC, SDS-PAGE, LC-MS/MS, NMR.

scholarly journals Systematic identification of engineered methionines and oxaziridines for efficient, stable, and site-specific antibody bioconjugation

2019 ◽  
Author(s):  
Susanna K. Elledge ◽  
Hai L. Tran ◽  
Alec H. Christian ◽  
Veronica Steri ◽  
Byron Hann ◽  
...  
Keyword(s):  
Specific Antibody ◽  
Xenograft Model ◽  
Antibody Engineering ◽  
Antibody Drug Conjugate ◽  
Site Specific ◽  
Drug Conjugates ◽  
Mouse Xenograft Model ◽  
Random Modification ◽  
The Stability ◽  
Antibody Drug

AbstractChemical modification of antibodies is one of the most important bioconjugations utilized by biologists and biotechnology. To date, the field has been dominated by random modification of lysines or more site-specific labeling of cysteines, each with attendant challenges. Recently we have developed oxaziridine chemistry for highly selective and efficient sulfimide modification of methionine called redox-activated chemical tagging (ReACT). Here, we systematically scanned methionines throughout one of the most popular antibody scaffolds, trastuzumab, for antibody engineering and drug conjugation. We tested the expression, reactivities, and stabilities of 123 single engineered methionines distributed over the surface of the antibody when reacted with oxaziridine. We found uniformly high expression for these mutants and generally good reaction efficiencies with the panel of oxaziridines. Remarkably, the stability to hydrolysis of the sulfimide varied more than ten-fold depending on temperature and the site of the engineered methionine. Interestingly, the most stable and reactive sites were those that were partially buried, likely because of their reduced access to water. There was also a ten-fold variation in stability depending on the nature of the oxaziridine, which we determined was inversely correlated with the electrophilic nature of the sulfimide. Importantly, the stabilities of the best analogs and antibody drug conjugate potencies were comparable to those reported for cysteine-maleimide modifications of trastuzumab. We also found our antibody drug conjugates to be potent in a breast cancer mouse xenograft model. These studies provide a roadmap for broad application of ReACT for efficient, stable, and site-specific antibody and protein bioconjugation.

Abstract 752: CovisoLinK: New bacterial transglutaminase Q-Tag substrate for the development of site specific antibody-drug conjugates

2018 ◽  
Author(s):  
Eva Sivado ◽  
Vincent Thomas ◽  
Meddy El Alaoui ◽  
Anne-Catherine Jallas ◽  
Mike R. Dyson ◽  
...  
Keyword(s):  
Specific Antibody ◽  
Site Specific ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Discovery of Pyrophosphate Diesters as Tunable, Soluble, and Bioorthogonal Linkers for Site-Specific Antibody–Drug Conjugates

2016 ◽  
Vol 138 (4) ◽  
pp. 1430-1445 ◽  
Author(s):  
Jeffrey C. Kern ◽  
Mark Cancilla ◽  
Deborah Dooney ◽  
Kristen Kwasnjuk ◽  
Rena Zhang ◽  
...  
Keyword(s):  
Specific Antibody ◽  
Site Specific ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

scholarly journals Synthesis of site-specific antibody-drug conjugates by ADP-ribosyl cyclases

2020 ◽  
Vol 6 (23) ◽  
pp. eaba6752 ◽  
Author(s):  
Zhefu Dai ◽  
Xiao-Nan Zhang ◽  
Fariborz Nasertorabi ◽  
Qinqin Cheng ◽  
Jiawei Li ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Reaction Times ◽  
Single Step ◽  
Her2 Positive ◽  
Site Specific ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Most of the current antibody-drug conjugates (ADCs) in clinic are heterogeneous mixtures. To produce homogeneous ADCs, established procedures often require multiple steps or long reaction times. The introduced mutations or foreign sequences may cause high immunogenicity. Here, we explore a new concept of transforming CD38 enzymatic activity into a facile approach for generating site-specific ADCs. This was achieved through coupling bifunctional antibody-CD38 fusion proteins with designer dinucleotide-based covalent inhibitors with stably attached payloads. The resulting adenosine diphosphate–ribosyl cyclase–enabled ADC (ARC-ADC) with a drug-to-antibody ratio of 2 could be rapidly generated through single-step conjugation. The generated ARC-ADC targeting human epidermal growth factor receptor 2 (HER2) displays excellent stability and potency against HER2-positive breast cancer both in vitro and in vivo. This proof-of-concept study demonstrates a new strategy for production of site-specific ADCs. It may provide a general approach for the development of a novel class of ADCs with potentially enhanced properties.

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