Antibody–Drug Conjugates: Empowering Antibodies for the Fight Against Cancer

Denevault‐Sabourin, Caroline; Bryden, Francesca; Viaud‐Massuard, Marie‐Claude; Joubert, Nicolas

doi:10.1002/9783527814695.ch3

Cited by 5 publications

(4 citation statements)

References 58 publications

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“…Scheme 3. Adcetris ® , Polivy ® or Padcev ® mechanism of action: (1) binding to a specific Ag, followed by internalization of the ADC-Ag complex according to a clathrin-dependent mechanism; (2) transfer to the endosomes then (3) to the lysosomes; (4) linker cleavage in the lysosomes takes place between the peptide sequence (ValCit) and the self-immolative spacer (PAB); (5) transfer of MMAE into the cytoplasm; (6) MMAE can also be released before internalization, then (7) enter the targeted cell (or a nearby tumor cell) and (8) intracellular or extracellular MMAE release is followed by tubulin targeting. In parallel to 8, (9) diffusion of another MMAE in neighboring tumor cells not targeted by the ADC to obtain a bystander killing effect and (10) all the previous steps lead to tumor cell death.…”

Section: Adcetris ® Polivy ® and The Second-generation Cleavable LImentioning

confidence: 99%

“…Several dozen bioconjugation technologies based on cysteine residues, non-natural amino acids or patterns introduced by molecular engineering have been proposed in preclinical studies [6]. Finally, more tumor specific antigenic targets and optimized release mechanisms of the cytotoxic agent within the tumor have led to the development of more performant ADCs [7][8][9]. This review will focus on FDA-approved and late stage ADCs as well as their limitation including their toxicity and associated resistance mechanisms.…”

Section: Introduction/historymentioning

confidence: 99%

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Antibody–Drug Conjugates: The Last Decade

et al. 2020

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An armed antibody (antibody–drug conjugate or ADC) is a vectorized chemotherapy, which results from the grafting of a cytotoxic agent onto a monoclonal antibody via a judiciously constructed spacer arm. ADCs have made considerable progress in 10 years. While in 2009 only gemtuzumab ozogamicin (Mylotarg®) was used clinically, in 2020, 9 Food and Drug Administration (FDA)-approved ADCs are available, and more than 80 others are in active clinical studies. This review will focus on FDA-approved and late-stage ADCs, their limitations including their toxicity and associated resistance mechanisms, as well as new emerging strategies to address these issues and attempt to widen their therapeutic window. Finally, we will discuss their combination with conventional chemotherapy or checkpoint inhibitors, and their design for applications beyond oncology, to make ADCs the magic bullet that Paul Ehrlich dreamed of.

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Section: Adcetris ® Polivy ® and The Second-generation Cleavable LImentioning

confidence: 99%

Section: Introduction/historymentioning

confidence: 99%

Antibody–Drug Conjugates: The Last Decade

et al. 2020

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“…Conjugation through existing lysine residues ( e.g. , by amine-succinimidyl ester) is one of the most commonly used methods for ADC development. , This method generates ADCs with varying numbers of payloads from 0 to 9, presenting an easy-to-use strategy that has been applied in many successful anticancer ADCs on the market. , However, the exact number of payloads and their conjugation sites is not controllable. This might result in compromised drug potency because of the inconsistent solubility, stability, and target-binding ability between the molecules .…”

Section: Introductionmentioning

confidence: 99%

Site-Specific Antibody Conjugation Using Modified Bisected N-Glycans: Method Development and Potential toward Tunable Effector Function

Hsu,

Nourzaie,

Tocher

et al. 2023

Bioconjugate Chem.

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Antibody−drug conjugates (ADCs) have garnered worldwide attention for disease treatment, as they possess high target specificity, a long half-life, and outstanding potency to kill or modulate the functions of targets. FDA approval of multiple ADCs for cancer therapy has generated a strong desire for novel conjugation strategies with high biocompatibility and controllable bioproperties. Herein, we present a bisecting glycan-bridged conjugation strategy that enables site-specific conjugation without the need for the oligosaccharide synthesis and genetic engineering of antibodies. Application of this method is demonstrated by conjugation of anti-HER2 human and mouse IgGs with a cytotoxic drug, monomethyl auristatin E. The glycan bridge showed outstanding stability, and the resulting ADCs eliminated HER2-expressing cancer cells effectively. Moreover, our strategy preserves the feasibility of glycan structure remodeling to fine-tune the immunogenicity and pharmacokinetic properties of ADCs through glycoengineering.

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“…Antibody–drug conjugates (ADCs) combine a highly potent cytotoxic agent (drug or payload) conjugated through a suitably constructed linker onto a monoclonal antibody (mAb) directed to a tumor-selective antigen [ 1 , 2 , 3 , 4 ]. The aims of this approach are to reduce systemic toxicity while enhancing antitumor efficacy.…”

Section: Introductionmentioning

confidence: 99%

Intra-Domain Cysteines (IDC), a New Strategy for the Development of Original Antibody Fragment–Drug Conjugates (FDCs)

et al. 2022

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Antibody–drug conjugates (ADCs) derived from a full immunoglobulin-G (IgG) are associated with suboptimal solid-tumor penetration and Fc-mediated toxicities. Antibody fragment–drug conjugates (FDCs) could be an alternative. Nevertheless, innovative solutions are needed to implant cysteines as conjugation sites in the single-chain fragment variable (scFv) format, which is the backbone from which many other antibody formats are built. In addition, the bioconjugation site has the utmost importance to optimize the safety and efficacy of bioconjugates. Our previous intra-tag cysteine (ITC) strategy consisted of introducing a bioconjugation motif at the C-terminal position of the 4D5.2 scFv, but this motif was subjected to proteolysis when the scFv was produced in CHO cells. Considering these data, using three intra-domain cysteine (IDC) strategies, several parameters were studied to assess the impact of different locations of a site-specific bioconjugation motif in the variable domains of an anti-HER2 scFv. In comparison to the ITC strategy, our new IDC strategy allowed us to identify new fragment–drug conjugates (FDCs) devoid of proteolysis and exhibiting enhanced stability profiles, better affinity, and better ability to kill selectively HER2-positive SK-BR-3 cells in vitro at picomolar concentrations. Thus, this work represents an important optimization step in the design of more complex and effective conjugates.

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Antibody–Drug Conjugates: Empowering Antibodies for the Fight Against Cancer

Cited by 5 publications

References 58 publications

Antibody–Drug Conjugates: The Last Decade

Antibody–Drug Conjugates: The Last Decade

Site-Specific Antibody Conjugation Using Modified Bisected N-Glycans: Method Development and Potential toward Tunable Effector Function

Intra-Domain Cysteines (IDC), a New Strategy for the Development of Original Antibody Fragment–Drug Conjugates (FDCs)

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