Antibody–Drug Conjugates: Future Directions in Clinical and Translational Strategies to Improve the Therapeutic Index

Coats, Steven; Williams, Marna; Kebble, Benjamin; Dixit, Rakesh; Tseng, Leo; Yao, Nai-Shun; Tice, David A.; Soria, Jean‐Charles

doi:10.1158/1078-0432.ccr-19-0272

Cited by 234 publications

(185 citation statements)

References 75 publications

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“…Antibody-drug conjugates (ADCs), using antibodies to selectively deliver potent cytotoxins to tumor cells, have recently become a promising next-generation of anticancer drugs [1,2]. At present, seven ADCs (Mylotarg ® , Adcetris ® , Kadcyla ® , Besponsa ® , Polivy ® , Padcev ® , and Enhertu ® ) have been approved to treat many types of cancer, while at least 80 ADCs are in clinical trials [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

“…Although the current MMAE-based ADCs with cleavable linkers have achieved great success in clinical applications, there are still limitations in the design concept and the antitumor activity should always be balanced by safety considerations [5,11]. These ADCs work by releasing MMAE in its unmodified form under the catalysis of enzymes (cathepsin B, etc.)…”

Section: Introductionmentioning

confidence: 99%

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Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety

Wang¹,

Liu²,

Fan³

et al. 2020

Cancers

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Monomethyl auristatin E (MMAE) is the most popular and widely used cytotoxin in the development of antibody-drug conjugates (ADCs). However, current MMAE-based ADCs are all constructed using cleavable linkers, and this design concept still has insurmountable drawbacks. Their potential instabilities and lipophilic MMAE-induced “bystander effect” inevitably increase the toxicity to normal tissues. Herein, we overturn previous negative views of MMAE-based ADCs with non-cleavable linkers and propose using ionized L-Cysteine (Cys)-linker-MMAE as a novel payload, which can ingeniously enrich and enter tumor cells through receptor-mediated endocytosis of antibodies while its lower permeability helps to avoid further off-target toxicity. We demonstrate that Cys-linker-MMAE maintains high potency similar to free MMAE at the tubulin molecular level and can also be efficiently released in target cells. As a result, the preferred ADC (mil40-15) not only exhibits ideal plasma stability and maintains potent cytotoxicity as MMAE (IC50: 10−11 M), but also shows improved safety with lower bystander toxicity (IC50: 10−9 M), its maximum tolerated dose approaching the level of the naked antibody (160 mg/kg). This study indicated that Cys-linker-MMAE has the potential as a potent payload for ADCs, which is expected to provide novel strategies for the development of MMAE-based ADCs.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety

Wang¹,

Liu²,

Fan³

et al. 2020

Cancers

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“…Antibody-targeted therapies including antibody-drug conjugates (ADC) represent a promising 573 approach for specific homing, increased uptake and drug retention at tumor sites while reducing 574 drug exposure to normal tissues and the associated dose-limiting side effects (Coats et al, 2019). 575…”

Section: Cell Surface Biomarkers For Targeted Therapy In Relation Witmentioning

confidence: 99%

SCLC_CellMiner: Integrated Genomics and Therapeutics Predictors of Small Cell Lung Cancer Cell Lines based on their genomic signatures

Tlemsani

Girard

Roper

et al. 2020

Preprint

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SummaryModel systems are necessary to understand the biology of SCLC and develop new therapies against this recalcitrant disease. Here we provide the first online resource, CellMiner-SCLC (https://discover.nci.nih.gov/SclcCellMinerCDB) incorporating 118 individual SCLC cell lines and extensive omics and drug sensitivity datasets, including high resolution methylome performed for the purpose of the current study. We demonstrate the reproducibility of the cell lines and genomic data across the CCLE, GDSC, CTRP, NCI and UTSW datasets. We validate the SCLC classification based on four master transcription factors: NEUROD1, ASCL1, POU2F3 and YAP1 (NAPY classification) and show transcription networks connecting each them with their downstream and upstream regulators as well as with the NOTCH and HIPPO pathways and the MYC genes (MYC, MYCL1 and MYCN). We find that each of the 4 subsets express specific surface markers for antibody-targeted therapies. The SCLC-Y cell lines differ from the other subsets by expressing the NOTCH pathway and the antigen-presenting machinery (APM), and responding to mTOR and AKT inhibitors. Our analyses suggest the potential value of NOTCH activators, YAP1 inhibitors and immune checkpoint inhibitors in SCLC-Y tumors that can now be independently validated.Graphical AbstractHighlightsSCLC-CellMiner provides the most extensive SCLC resource in terms of number of cell lines (118 cell lines), extensive omics data (exome, microarray, RNA-seq, copy number, methylomes and microRNA) and drug sensitivity testing.We find evidence of distinct epigenetic profile of SCLC cell lines (global hypomethylation and histone gene methylation), which is consistent with their plasticity.Transcriptome analyses demonstrate the coherent transcriptional networks associated with the 4 main genomic subgroups (NEUROD1, ASCL1, POU2F3 & YAP1 = NAPY classification) and their connection with the NOTCH and HIPPO signaling pathways.SCLC-CellMiner provides a conceptual framework for the selection of therapies for SCLC in a personalized fashion allowing putative biomarkers according molecular classifications and molecular characteristics.SCLC-Y cell lines differ from the other cancer cell lines; their transcriptome resemble NSCLC cell lines. YAP1 cell lines while being the most resistant to standard of care treatments (etoposide, cisplatin and topotecan) respond to mTOR and AKT inhibitors and present native immune predisposition suggesting sensitivity to immune checkpoint inhibitors.

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“…Clinical results from the approved ADCs and those in clinical development suggest that the anticipated improvement in Therapeutic Index (TI) has not yet been realized [24], in part due to the toxic effects of the first-generation payloads which target DNA (i.e., calicheamicins, PBD dimers) or tubulin (maytansinoids, auristatins) [25]. Tubulin inhibitors (i.e., the auristatins and maytansinoids) only kill proliferating cells, and may lack efficacy in killing non-dividing tumor cells [26,27].…”

Section: Introductionmentioning

confidence: 99%

A Novel Antibody-Drug Conjugate (ADC) Delivering a DNA Mono-Alkylating Payload to Chondroitin Sulfate Proteoglycan (CSPG4)-Expressing Melanoma

Hoffmann

Crescioli

Mele

et al. 2020

Cancers

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Despite emerging targeted and immunotherapy treatments, no monoclonal antibodies or antibody-drug conjugates (ADCs) directly targeting tumor cells are currently approved for melanoma therapy. The tumor-associated antigen chondroitin sulphate proteoglycan 4 (CSPG4), a neural crest glycoprotein over-expressed on 70% of melanomas, contributes to proliferative signaling pathways, but despite highly tumor-selective expression it has not yet been targeted using ADCs. We developed a novel ADC comprising an anti-CSPG4 antibody linked to a DNA minor groove-binding agent belonging to the novel pyrridinobenzodiazepine (PDD) class. Unlike conventional DNA-interactive pyrrolobenzodiazepine (PBD) dimer payloads that cross-link DNA, PDD-based payloads are mono-alkylating agents but have similar efficacy and substantially enhanced tolerability profiles compared to PBD-based cross-linkers. We investigated the anti-tumor activity and safety of the anti-CSPG4-(PDD) ADC in vitro and in human melanoma xenografts. Anti-CSPG4-(PDD) inhibited CSPG4-expressing melanoma cell growth and colony formation and triggered apoptosis in vitro at low nanomolar to picomolar concentrations without off-target Fab-mediated or Fc-mediated toxicity. Anti-CSPG4-(PDD) restricted xenograft growth in vivo at 2 mg/kg doses. One 5 mg/kg injection triggered tumor regression in the absence of overt toxic effects or of acquired residual tumor cell resistance. This anti-CSPG4-(PDD) can deliver a highly cytotoxic DNA mono-alkylating payload to CSPG4-expressing tumors at doses tolerated in vivo.

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Antibody–Drug Conjugates: Future Directions in Clinical and Translational Strategies to Improve the Therapeutic Index

Cited by 234 publications

References 75 publications

Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety

Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety

SCLC_CellMiner: Integrated Genomics and Therapeutics Predictors of Small Cell Lung Cancer Cell Lines based on their genomic signatures

A Novel Antibody-Drug Conjugate (ADC) Delivering a DNA Mono-Alkylating Payload to Chondroitin Sulfate Proteoglycan (CSPG4)-Expressing Melanoma

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