Site-selective modification strategies in antibody–drug conjugates

Walsh, Stephen J.; Bargh, Jonathan D; Dannheim, Friederike M.; Hanby, Abigail R.; Seki, Hikaru; Counsell, Andrew J.; Ou, Xiaoxu; Fowler, Elaine; Ashman, Nicola; Takada, Yuri; Isidro‐Llobet, Albert; Parker, Jeremy S.; Carroll, Jason S.; Spring, David R.

doi:10.1039/d0cs00310g

Cited by 298 publications

(290 citation statements)

References 357 publications

(410 reference statements)

Supporting

Mentioning

289

Contrasting

Unclassified

Order By: Relevance

“…The expression of this protein is done in the presence of a special tRNA/aminoacyl-tRNA-synthetase pair which can insert the unnatural amino acid at the amber stop codon site [21]. These and other site-specific conjugation methods were reviewed elsewhere [26]. In this review we will summarize some of the enzyme-based conjugation approaches.…”

Section: Conjugation Methodsmentioning

confidence: 99%

Toward Homogenous Antibody Drug Conjugates Using Enzyme-Based Conjugation Approaches

et al. 2021

View full text Add to dashboard Cite

In the last few decades, antibody-based diagnostic and therapeutic applications have been well established in medicine and have revolutionized cancer managements by improving tumor detection and treatment. Antibodies are unique medical elements due to their powerful properties of being able to recognize specific antigens and their therapeutic mechanisms such as blocking specific pathways, antibody-dependent cellular cytotoxicity, and complement-dependent cytotoxicity. Furthermore, modification techniques have paved the way for improving antibody properties and to develop new classes of antibody-conjugate-based diagnostic and therapeutic agents. These techniques allow arming antibodies with various effector molecules. However, these techniques are utilizing the most frequently used amino acid residues for bioconjugation, such as cysteine and lysine. These bioconjugation approaches generate heterogeneous products with different functional and safety profiles. This is mainly due to the abundance of lysine and cysteine side chains. To overcome these limitations, different site-direct conjugation methods have been applied to arm the antibodies with therapeutic or diagnostics molecules to generate unified antibody conjugates with tailored properties. This review summarizes some of the enzyme-based site-specific conjugation approaches.

show abstract

Section: Conjugation Methodsmentioning

confidence: 99%

Toward Homogenous Antibody Drug Conjugates Using Enzyme-Based Conjugation Approaches

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Their strategy exploits the enzyme sortase A (Srt A) that cleaves the amide bond between threonine and glycine residues in the LPXTG (X = any amino acid) pentapeptide motif ( Figure 60 c). Then, it catalyzes the linking of glycine-derived payloads to the newly generated C-terminus, generating a peptide bond at physiological temperature and pH [ 140 ]. This approach was applied to different antibodies such as anti-CD30 and anti-Her2 with penta-glycine tagged linkers containing maytansine and MMAE [ 141 ].…”

Section: Bioconjugationmentioning

confidence: 99%

The Chemistry Behind ADCs

et al. 2021

View full text Add to dashboard Cite

Combining the selective targeting of tumor cells through antigen-directed recognition and potent cell-killing by cytotoxic payloads, antibody-drug conjugates (ADCs) have emerged in recent years as an efficient therapeutic approach for the treatment of various cancers. Besides a number of approved drugs already on the market, there is a formidable follow-up of ADC candidates in clinical development. While selection of the appropriate antibody (A) and drug payload (D) is dictated by the pharmacology of the targeted disease, one has a broader choice of the conjugating linker (C). In the present paper, we review the chemistry of ADCs with a particular emphasis on the medicinal chemistry perspective, focusing on the chemical methods that enable the efficient assembly of the ADC from its three components and the controlled release of the drug payload.

show abstract

“…Site-specific methods are proposed to optimize the DAR and maintain favorable pharmacokinetics while maximizing payloads in the development of ADCs. Several site-specific conjugation approaches that utilize integrated non-natural amino acids, engineered cysteine residues [ 37 ] or enzymatic modifications, including transglutaminases [ 38 ], sortase A [ 39 ], glycosyltransferase [ 40 ] and formylglycine-generating enzyme [ 41 ], have been reported. The chemoenzymatic approach can harvest a high yield of ADCs with suitable DARs and attractive conjugation efficiency by achieving site-specific conjugation and generating precisely controlled modification sites [ 42 ].…”

Section: Engineering Adcsmentioning

confidence: 99%

Antibody-drug conjugates for the treatment of lymphoma: clinical advances and latest progress

2021

View full text Add to dashboard Cite

Antibody-drug conjugates (ADCs) are a promising class of immunotherapies with the potential to specifically target tumor cells and ameliorate the therapeutic index of cytotoxic drugs. ADCs comprise monoclonal antibodies, cytotoxic payloads with inherent antitumor activity, and specialized linkers connecting the two. In recent years, three ADCs, brentuximab vedotin, polatuzumab vedotin, and loncastuximab tesirine, have been approved and are already establishing their place in lymphoma treatment. As the efficacy and safety of ADCs have moved in synchrony with advances in their design, a plethora of novel ADCs have garnered growing interest as treatments. In this review, we provide an overview of the essential elements of ADC strategies in lymphoma and elucidate the up-to-date progress, current challenges, and novel targets of ADCs in this rapidly evolving field.

show abstract

Site-selective modification strategies in antibody–drug conjugates

Abstract: Antibody–drug conjugates (ADCs) harness the highly specific targeting capabilities of an antibody to deliver a cytotoxic payload to specific cell types. This review summarises the advances made in the construction of homogenous ADCs.

Cited by 298 publications

References 357 publications

Toward Homogenous Antibody Drug Conjugates Using Enzyme-Based Conjugation Approaches

Toward Homogenous Antibody Drug Conjugates Using Enzyme-Based Conjugation Approaches

The Chemistry Behind ADCs

Antibody-drug conjugates for the treatment of lymphoma: clinical advances and latest progress

Contact Info

Product

Resources

About