Antibody-based therapeutics to watch in 2011

Reichert, Janice M.

doi:10.4161/mabs.3.1.13895

Cited by 215 publications

(176 citation statements)

References 68 publications

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“…Most of the mAbs approved for clinical use are full-size (7,9,10). However, fullsize antibodies exhibit poor penetration into tissues, especially solid tumors, and also poor or absent binding to regions of some antigens that are occluded and can only be accessed by molecules of smaller size (11)(12)(13).…”

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confidence: 99%

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Soluble Monomeric IgG1 Fc

Ying

Chen

Gong

et al. 2012

Journal of Biological Chemistry

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confidence: 99%

“…Therapeutic monoclonal antibodies have been improved gradually during the past two decades (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Most of the mAbs approved for clinical use are full-size (7,9,10).…”

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confidence: 99%

Soluble Monomeric IgG1 Fc

Ying

Chen

Gong

et al. 2012

Journal of Biological Chemistry

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“…O ver the past decades, several anticancer Ab therapeutic agents have been developed and tested in the clinic, and 12 are currently approved for use in oncology (1)(2)(3)(4)(5)(6). Many of these agents affect tumor growth by interfering with receptor signaling.…”

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confidence: 99%

Glycoengineering of Therapeutic Antibodies Enhances Monocyte/Macrophage-Mediated Phagocytosis and Cytotoxicity

Herter

Birk

Klein

et al. 2014

The Journal of Immunology

133

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Therapeutic Abs possess several clinically relevant mechanisms of action including perturbation of tumor cell signaling, activation of complement-dependent cytotoxicity, Ab-dependent cellular cytotoxicity (ADCC), Ab-dependent cellular phagocytosis (ADCP), and induction of adaptive immunity. In view of the important role of phagocytic lineage cells in the mechanism of action of therapeutic Abs, we analyzed FcγR receptor-dependent effector functions of monocytes and macrophages triggered by glycoengineered (GE) Abs (having enhanced FcγRIIIa [CD16a] binding affinity) versus their wild-type (WT) counterparts under different experimental conditions. We first defined the precise FcγR repertoire on classical and nonclassical intermediate monocytes—M1 and M2c macrophage populations. We further show that WT and GE Abs display comparable binding and induce similar effector functions (ADCC and ADCP) in the absence of nonspecific, endogenous IgGs. However, in the presence of these IgGs (i.e., in a situation that more closely mimics physiologic conditions), GE Abs display significantly superior binding and promote stronger monocyte and macrophage activity. These data show that in addition to enhancing CD16a-dependent NK cell cytotoxicity, glycoengineering also enhances monocyte and macrophage phagocytic and cytotoxic activities through enhanced binding to CD16a under conditions that more closely resemble the physiologic setting.

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“…1 Trastuzumab ematansine (T-DM1) 2 for human epidermal growth factor receptor 2 (Her-2)-positive breast cancer and brentuximab vedotin (SGN-35) 3 for relapsed or refractory CD30-positive lymphoproliferative disorders are now in phase 3 clinical trials as effective ADCs. 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.…”

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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-based therapeutics to watch in 2011

Cited by 215 publications

References 68 publications

Soluble Monomeric IgG1 Fc

Soluble Monomeric IgG1 Fc

Glycoengineering of Therapeutic Antibodies Enhances Monocyte/Macrophage-Mediated Phagocytosis and Cytotoxicity

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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