Antibody-Drug Conjugates: The 21st Century Magic Bullets for by Jeffrey Wang, Wei-Chiang Shen, Jennica L. Zaro

By Jeffrey Wang, Wei-Chiang Shen, Jennica L. Zaro

This authoritative quantity offers a holistic photo of antibody-drug conjugates (ADCs). Fourteen finished chapters are divided into six sections together with an advent to ADCs, the ADC build, improvement concerns, panorama, IP and pharmacoeconomics, case experiences, and the way forward for the sector. The booklet examines every thing from the choice of the antibody, the drug, and the linker to a dialogue of developmental concerns comparable to formulations, bio-analysis, pharmacokinetic-pharmacodynamic relationships, and toxicological and regulatory demanding situations. It additionally explores pharmacoecomonics and highbrow houses, together with lately issued patents and the price research of drug remedy. Case reviews are offered for the 3 ADCs that experience acquired FDA approval: gemtuzumab ozogamicin (Mylotarg®), Brentuximab vedotin (Adcetris®), and ado-trastuzumab emtansine (Kadcyla®), in addition to an ADC in late-stage scientific trials, glembatumumab vedotin (CDX-011). eventually, the quantity offers a point of view via the editors at the destiny instructions of ADC improvement and medical purposes. Antibody-Drug Conjugates is a realistic and systematic source for scientists, professors, and scholars drawn to increasing their wisdom of state-of-the-art study during this intriguing field.

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Extra info for Antibody-Drug Conjugates: The 21st Century Magic Bullets for Cancer

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However, the tumor microenvironment is often weakly acidic, which would reduce the cell-surface binding of pH-sensitive ADCs. Further investigation is required to understand the optimal degree of pH dependence for ADCs targeted to solid tumors, such that binding at the cell surface is not compromised. 3 Engineering Fc-Mediated Interactions Fc-mediated effector function accounts for most of the in vivo efficacy imparted by unconjugated mAbs in cancer therapy. However, the role of Fc effector function in inhibition of tumor growth by an ADC in the clinic remains unclear.

28 M. Ritchie et al. 0 than at neutral pH has attracted interest as a method for manipulation of the kinetics of antibody delivery to the lysosome (Chaparro-Riggers et al. 2012). The pH dependence is achieved through the introduction of histidine residues at or near the antibody/antigen binding interface. 0 and, if placed correctly, can have a profound effect on binding affinity in different pH environments. 0), while retaining binding to the FcRn receptor, which returns them to the cell surface and prevents degradation in the lysosome (Chaparro-Riggers et al.

1988) or pokeweed antiviral protein (Weltman et al. 1987) or genetic fusions of Pseudomonas exotoxin A to an antikappa single-domain antibody (Kellner et al. 2011) or to the Z domain of Staphylococcus protein A (Mazor et al. 2007). Commercially available secondary antibodies conjugated to the ribosome-inactivating protein saporin have been widely used to confirm antibody internalization (Kohls and Lappi 2000; Nguyen et al. 2006; Fransson and Borrebaeck 2009; Sawada et al. 2011). Antibodies can be incubated with saporin-conjugated antimouse, antirat, or antihuman reagents and then incubated with tumor cells for 3–4 days.

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