Antibody drug-conjugates targeting the tumor vasculature

Gerber, Hans‐Peter; Senter, Peter D.; Grewal, Iqbal S.

doi:10.4161/mabs.1.3.8515

Cited by 66 publications

(57 citation statements)

References 90 publications

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“…Early antibody drug conjugates employed acid hydrazone linkers; however, the major pitfall of this class of linkers is their proclivity to undergo spontaneous cleavage (5). More recent linkers employ disulfide and peptidic moieties, as described above, which exhibit improved stability in circulation (5,55).…”

Section: Linkersmentioning

confidence: 99%

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Antibody Drug Conjugates: Preclinical Considerations

Bornstein

2015

AAPS J

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ABSTRACT. The development path for antibody drug conjugates (ADCs) is more complex and challenging than for unmodified antibodies. While many of the preclinical considerations for both unmodified and antibody drug conjugates are shared, special considerations must be taken into account when developing an ADC. Unlike unmodified antibodies, an ADC must preferentially bind to tumor cells, internalize, and traffic to the appropriate intracellular compartment to release the payload. Parameters that can impact the pharmacological properties of this class of therapeutics include the selection of the payload, the type of linker, and the methodology for payload drug conjugation. Despite a plethora of in vitro assays and in vivo models to screen and evaluate ADCs, the challenge remains to develop improved preclinical tools that will be more predictive of clinical outcome. This review will focus on preclinical considerations for clinically validated small molecule ADCs. In addition, the lessons learned from Mylotarg®, the first in class FDA-approved ADC, are highlighted.

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Section: Linkersmentioning

confidence: 99%

“…Parameters that can impact the pharmacological properties of this class of therapeutics include the selection of the payload, the type of linker, and the methodology for payload drug conjugation ( Fig. 1) (5).…”

Section: Introductionmentioning

confidence: 99%

Antibody Drug Conjugates: Preclinical Considerations

Bornstein

2015

AAPS J

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“…The results of such combinations are more targeted and efficacious novel biotherapeutic products. [1][2][3][4][5][6] By combining the target-specific capabilities of antibodies with the tumor-killing ability of cytotoxic molecules, ADCs allow sensitive discrimination between healthy and tumor tissue and work as "magic bullets" for targeted cancer therapy. 4 So far, 3 ADCs have been approved by the US Food and Drug Administration, and 2 of these are currently marketed: brentuximab vedotin 7 (Adcetris Ò ) and ado-trastuzumab emtansine 8,9 (T-DM1, Kadcyla Ò ).…”

Section: Introductionmentioning

confidence: 99%

The impact of trisulfide modification of antibodies on the properties of antibody-drug conjugates manufactured using thiol chemistry

Liu

Chen

Dushime

et al. 2017

mAbs

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Antibody-drug conjugates (ADCs) are promising biotherapeutic agents for the treatment of cancer. The careful monitoring of critical quality attributes is important for ADCs' development, manufacturing and production. In this work, the effect of the presence of a trisulfide bond in the monoclonal antibody (mAb) conjugated to DM4 cytotoxic payload through a disulfide-bond linker sulfo-SPDB (sSPDB) was investigated. Three lots of antibody containing variable levels of trisulfide bonds were used. The identity and levels of trisulfide bonds were determined by liquid chromatography/ mass spectrometry (MS)/MS analysis. The antibodies were conjugated to sSPDB-DM4 to generate ADCs. Further analysis indicated that the drug-to-antibody ratio (DAR) value, a critical quality attribute, slightly increased for the conjugates made from antibody containing higher levels of trisulfide bond. Also, higher fragmentation levels were observed in the conjugates with more trisulfide bond. Detailed characterization by MS revealed that a small amount of DM4 payload was directly attached to inter-chain cysteine residues by disulfide or trisulfide bonds. Overall, our investigation indicated that the trisulfide bond present in the mAb could react with DM4 during the conjugation process. Therefore, the presence of trisulfide bonds in the antibody moiety should be carefully monitored and well controlled during the development of a maytansinoid ADC.

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“…4 ADCs will have an important role in overcoming some types of refractory cancers and will contribute to the field of tumor vascular targeting. 5 An essential property of ADCs is that the mAb should be efficiently internalized into the cell where the cytotoxic effects of anticancer drugs occur. 1 The isolation of mAbs with high cellinternalizing activity (cell-internalizing mAbs) is a limiting factor in the development of ADCs.…”

Section: Introductionmentioning

confidence: 99%

Robo4 is an effective tumor endothelial marker for antibody-drug conjugates based on the rapid isolation of the anti-Robo4 cell-internalizing antibody

Yoshikawa

Mukai

Okada

et al. 2013

Blood

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• First therapeutic application that targets Robo4 on the tumor blood vasculature • High-throughput screening system to isolate cellinternalizing monoclonal antibodies useful to develop effective antibody-drug conjugatesMonoclonal antibodies (mAbs) that are internalized into cells are a current focus in the development of antibody-drug conjugates (ADCs). We describe a phage display-based high-throughput screening system to rapidly isolate cellinternalizing mAbs. We simultaneously examined the cell-internalizing activities of several hundred independent mAbs and successfully isolated cell-internalizing mAbs against the tumor endothelial markers Roundabout homolog 4 (Robo4) and vascular endothelial growth factor receptor 2 (VEGFR2). Tumor accumulation of mAbs with high cell-internalizing activity was significantly higher than that of mAbs with low cell-internalizing activity. Furthermore, the antitumor effects of ADCs of mAbs with high cell-internalizing activity were significantly stronger than those of mAbs with low cell-internalizing activity. Although anti-VEGFR2 therapy caused a significant loss of body weight, anti-Robo4 therapy did not. These findings indicate that cell-internalizing activity plays an important role in the biodistribution and therapeutic effects of ADCs. Further, Robo4 can be an effective marker for tumor vascular targeting. (Blood. 2013;121 (14):2804-2813

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Antibody drug-conjugates targeting the tumor vasculature

Cited by 66 publications

References 90 publications

Antibody Drug Conjugates: Preclinical Considerations

Antibody Drug Conjugates: Preclinical Considerations

The impact of trisulfide modification of antibodies on the properties of antibody-drug conjugates manufactured using thiol chemistry

Robo4 is an effective tumor endothelial marker for antibody-drug conjugates based on the rapid isolation of the anti-Robo4 cell-internalizing antibody

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