Antibody–drug conjugates come of age in oncology

Dumontet, Charles; Reichert, Janice M.; Senter, Peter D.; Lambert, John M.; Beck, Alain

doi:10.1038/s41573-023-00709-2

Cited by 253 publications

(147 citation statements)

References 229 publications

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“…The paradigm enediyne, calicheamicin 3, has been studied and used for > 30 years in pioneering applications of ADCs for cancer chemotherapy. [13][14][15][16] Extensive investigations have identified antibodies that selectively bind cellular antigens that are differentially and highly represented on cancer cells while parallel developments in increasingly sophisticated linker technologies have facilitated internalization and intracellular release of highly cytotoxic agents such as enediynes. Two of the 14 known enediynes are on the FDA-approved drug list for cancer treatment, with calicheamicin-based Mylotarg 1 (Figure 1,a; CMA-676, gemtuzumab ozogamicin) being the first-in-class antibody -drug conjugate (ADC) approved by the FDA for the treatment of first relapse of CD33-positive acute myeloid leukemia.…”

Section: Introductionmentioning

confidence: 99%

“…Today more than a dozen ADCs are marketed worldwide and dozens more are in clinical trials. The paradigm enediyne, calicheamicin 3 , has been studied and used for >30 years in pioneering applications of ADCs for cancer chemotherapy [13–16] . Extensive investigations have identified antibodies that selectively bind cellular antigens that are differentially and highly represented on cancer cells while parallel developments in increasingly sophisticated linker technologies have facilitated internalization and intracellular release of highly cytotoxic agents such as enediynes.…”

Section: Introductionmentioning

confidence: 99%

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Dynemicin A Derivatives as Potential Cancer Chemotherapeutics by Mutasynthesis

Pal,

Alley,

Cohen

et al. 2023

Helvetica Chimica Acta

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The enediyne antitumor antibiotics have remarkable structures and exhibit potent DNA cleavage properties that have inspired continued interest as cancer therapeutics. Their complex structures and high reactivity, however, pose formidable challenges to their production and development in the clinic. We report here proof‐of‐concept studies using a mutasynthesis strategy to combine chemical synthesis of select modifications to a key iodoanthracene‐g‐thiolactone intermediate in the biosynthesis of dynemicin A and all other known anthraquinone‐fused enediynes (AFEs). By chemical complementation of a mutant bacterial producer that is incapable of synthesizing this essential building block, we show that derivatives of dynemicin can be prepared substituted in the A‐ring of the anthraquinone motif. In the absence of competition from native production of this intermediate, the most efficient utilization of these externally‐supplied structural analogues for precursor‐directed biosynthesis becomes possible. To achieve this goal, we describe the required ∆orf15 blocked mutant and a general synthetic route to a library of iodoanthracene structural variants. Their successful incorporation opens the door to enhancing DNA binding and tuning the bioreductive activation of the modified enediynes for DNA cleavage.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dynemicin A Derivatives as Potential Cancer Chemotherapeutics by Mutasynthesis

Pal,

Alley,

Cohen

et al. 2023

Helvetica Chimica Acta

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show abstract

“…Antibody conjugates combine the exquisite targeting ability of antibodies with the diverse functionality of small molecules to generate a variety of constructs. Examples include antibody drug conjugates (ADCs), , radio-immunoconjugates, antibody nanoparticle conjugates and targeted imaging agents . With such systems, it has been identified that site-selective modification strategies result in superior conjugates, including exhibiting improved in vivo properties .…”

Section: Introductionmentioning

confidence: 99%

The Nitrile Bis-Thiol Bioconjugation Reaction

Patel,

Forte,

Bishop

et al. 2023

J. Am. Chem. Soc.

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Electron-poor aryl nitriles are promising reagents for bioconjugation due to their high electrophilicity and selectivity for reaction with thiols, albeit generally in a reversible manner. A transient species has previously been observed in such reactions, involving the addition of two thiols to the nitrile functional group, forming a tetrahedral amino dithioacetal (ADTA). In this work, the reaction of heteroaryl nitriles with bis-thiols is explored in an attempt to generate stable ADTAs, which could facilitate new bioconjugation protocols. By use of a 1,2-dithiol, or the incorporation of an electrophilic trap into the aryl nitrile design, the formation of stable products is achieved. The resultant "nitrile bis-thiol" (NBT) reaction is then explored in the context of protein modification, specifically to carry out antibody conjugation. By addition of these nitriles to the reduced disulfide bond of an antibody fragment, it is shown that, depending on the reagent design, cysteine-to-lysine transfer or disulfide bridged NBT products can be generated. Both represent site-selective conjugates and are shown to be stable when challenged with glutathione under physiological conditions and upon incubation in serum. Furthermore, the NBT reaction is tested in the more challenging context of a full antibody, and all four disulfide bonds are effectively modified by these new one-carbon bridging reagents. Overall, this reaction of heteroaryl-nitriles with bis-thiols is shown to be highly efficient and versatile, of tunable reversibility, and offers enticing prospects as a new addition to the toolbox of biocompatible "click"-type reactions.

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“…3 Likewise, the number of new antibody-drug conjugates reaching the clinical trial stage increased by nearly 5-fold in the last 5 years, with 21 currently in latestage development. 4 Whereas there were only a handful of new bispecific antibody (bsAb) clinical candidates per year in the first decade of this century, recent years have seen a remarkable growth for this modality class, with more than 50 bsAbs reaching clinical trials in 2021. 5 One example is rozibafusp alfa, a first-in-class bispecific IgG2-peptide fusion designed to inhibit inducible T-cell costimulator ligand and B-cell activating factor, for which the first clinical trial results in patients with rheumatoid arthritis are reported in this issue.…”

mentioning

confidence: 99%

Novel Therapeutic Modalities: The Future is Now

Choi,

Vinks,

van der Graaf

2023

Clin Pharma and Therapeutics

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Antibody–drug conjugates come of age in oncology

Cited by 253 publications

References 229 publications

Dynemicin A Derivatives as Potential Cancer Chemotherapeutics by Mutasynthesis

Dynemicin A Derivatives as Potential Cancer Chemotherapeutics by Mutasynthesis

The Nitrile Bis-Thiol Bioconjugation Reaction

Novel Therapeutic Modalities: The Future is Now

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