Site‐Specific and Stoichiometric Modification of Antibodies by Bacterial Transglutaminase

Jeger, Simone; Zimmermann, Kurt; Blanc, Alain; Grünberg, Jürgen; Honer, Michael; Hunziker, Peter; Struthers, Harriet; Schibli, Roger

doi:10.1002/anie.201004243

Cited by 283 publications

(290 citation statements)

References 17 publications

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“…Conveniently, bacterial mTGs are unable to modify glutamine residues in native IgG1s. Schibli and co-workers reported, however, that deglycosylating IgGs at N297 exposed a glutamine residue at the 295 position to enzymatic ligation to create ADCs with a DAR of 2 (31). Further, by producing a N297 to Q297 mutant IgG1, they were able to introduce two viable sites for enzymatic labeling to create ADCs with a DAR of 4 (31,32).…”

Section: Enzymatic Ligationmentioning

confidence: 99%

Antibody Drug Conjugates: Design and Selection of Linker, Payload and Conjugation Chemistry

McCombs

Owen

2015

AAPS J

268

199

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Abstract. Antibody drug conjugates (ADCs) have emerged as an important pharmaceutical class of drugs designed to harness the specificity of antibodies with the potency of small molecule therapeutics. The three main components of ADCs are the antibody, the linker, and the payload; the majority of early work focused intensely on improving the functionality of these pieces. Recently, considerable attention has been focused on developing methods to control the site and number of linker/drug conjugated to the antibody, with the aim of producing more homogenous ADCs. In this article, we review popular conjugation methods and highlight recent approaches including "click" conjugation and enzymatic ligation. We discuss current linker technology, contrasting the characteristics of cleavable and noncleavable linkers, and summarize the essential properties of ADC payload, centering on chemotherapeutics. In addition, we report on the progress in characterizing to determine physicochemical properties and on advances in purifying to obtain homogenous products. Establishing a set of selection and analytical criteria will facilitate the translation of novel ADCs and ensure the production of effective biosimilars.

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Section: Enzymatic Ligationmentioning

confidence: 99%

Antibody Drug Conjugates: Design and Selection of Linker, Payload and Conjugation Chemistry

McCombs

Owen

2015

AAPS J

268

199

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“…6B). A transglutaminase derived from Streptomyces mobaraensis catalyzes transpeptidation where a primary amine-containing linker is covalently attached to the primary amide side chain of a specific glutamine (Q295) within deglycosylated antibodies, resulting in ADCs with a defined DAR of 2 (one conjugation site per heavy chain) (Jeger et al, 2010;Dennler et al, 2014). An N297Q mutation prior to this conjugation provides two more reaction sites (DAR = 4).…”

Section: Transpeptidation Using Microbial Transglutaminasementioning

confidence: 99%

Antibody-Drug Conjugates in Head and Neck Cancer

Kim¹

2017

Korean J Otorhinolaryngol-Head Neck Surg

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The antibody-drug conjugate (ADC), a humanized or human monoclonal antibody conjugated with highly cytotoxic small molecules (payloads) through chemical linkers, is a novel therapeutic format and has great potential to make a paradigm shift in cancer chemotherapy. This new antibody-based molecular platform enables selective delivery of a potent cytotoxic payload to target cancer cells, resulting in improved efficacy, reduced systemic toxicity, and preferable pharmacokinetics (PK)/ pharmacodynamics (PD) and biodistribution compared to traditional chemotherapy. Boosted by the successes of FDA-approved Adcetris ® and Kadcyla ® , this drug class has been rapidly growing along with about 60 ADCs currently in clinical trials. In this article, we briefly review molecular aspects of each component (the antibody, payload, and linker) of ADCs, and then mainly discuss traditional and new technologies of the conjugation and linker chemistries for successful construction of clinically effective ADCs. Current efforts in the conjugation and linker chemistries will provide greater insights into molecular design and strategies for clinically effective ADCs from medicinal chemistry and pharmacology standpoints. The development of site-specific conjugation methodologies for constructing homogeneous ADCs is an especially promising path to improving ADC design, which will open the way for novel cancer therapeutics.

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“…Moreover, they could demonstrate that homogeneous antibody conjugates with a defined stoichiometry, i.e., exactly two payloads per antibody can be accomplished when the antibody was deglycosylated prior to the conjugation ( Figure 6C). The introduction of a N297Q mutation enabled them to express an aglycosylated antibody variant that displays four potential acyl-donor sites for MTGase, thereby doubling the number of payloads that can be attached to the antibody [136]. This concept has recently been used to generate ADCs that carry a defined number of toxins per antibody [137,138].…”

Section: Transglutaminasesmentioning

confidence: 99%

Antibody Conjugates: From Heterogeneous Populations to Defined Reagents

2015

Self Cite

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Monoclonal antibodies (mAbs) and their derivatives are currently the fastest growing class of therapeutics. Even if naked antibodies have proven their value as successful biopharmaceuticals, they suffer from some limitations. To overcome suboptimal therapeutic efficacy, immunoglobulins are conjugated with toxic payloads to form antibody drug conjugates (ADCs) and with chelating systems bearing therapeutic radioisotopes to form radioimmunoconjugates (RICs). Besides their therapeutic applications, antibody conjugates are also extensively used for many in vitro assays. A broad variety of methods to functionalize antibodies with various payloads are currently available. The decision as to which conjugation method to use strongly depends on the final purpose of the antibody conjugate. Classical conjugation via amino acid residues is still the most common method to produce antibody conjugates and is suitable for most in vitro applications. In recent years, however, it has become evident that antibody conjugates, which are generated via site-specific conjugation techniques, possess distinct advantages with regard to in vivo properties. Here, we give a comprehensive overview on existing and emerging strategies for the production of covalent and non-covalent antibody conjugates.

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Site‐Specific and Stoichiometric Modification of Antibodies by Bacterial Transglutaminase

Cited by 283 publications

References 17 publications

Antibody Drug Conjugates: Design and Selection of Linker, Payload and Conjugation Chemistry

Antibody Drug Conjugates: Design and Selection of Linker, Payload and Conjugation Chemistry

Antibody-Drug Conjugates in Head and Neck Cancer

Antibody Conjugates: From Heterogeneous Populations to Defined Reagents

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