Toxicities, ADCs

The ideal ADC target is highly expressed on tumor cells and absent on normal cells however, in reality, nearly all target proteins have some degree of normal tissue expression (Kessler et al 2006). This is problematic as any targetexpressing normal cell is potentially susceptible to ADC-mediated killing. The most well-known clinical example of on-target toxicity is bivatuzumab mertansine, an antihuman... 

While aitical to early safety evaluation, target expression alone is not snfficient to predict the potential for on-target toxicity of ADCs. This is dne to the fact that there are other factors—snch as anatomical location (i.e., membrane vs. 

About 88% of global CFA volume is ADC, with 5% in endothermic foaming agents and 7% of the volume in various other types [21]. However, endothermic CFAs are expected to grow slightly faster than exothermic CFAs due to both technical and regulatory concerns about exothermic CFA use. The desire by processors for finer cell strucmre and the prohibition by the European Food Safety Authority of the use of ADC in food contact materials due to its decomposition into toxic by-products are the driving forces for the future increased use of endothermic CFAs in many applications [21]. 

There are cases when a dedicated CV telemetry study may be the best option to assess target liability concerns for BPs. These include the presence of the therapeutic target in the CV system (e.g., cardiac myocytes, vascular endothelium, or vascular smooth muscle) or the emergence of CV findings in nonclinical toxicity studies or clinical trials. For example, observation of cardiac dysfunction in patients treated with trastuzumab, a mAb for treatment of breast cancer, prompted the sponsor to perform a long-term telemetry study in the cynomolgus monkey in attempts to model the human cardiac dysfunction (Klein and Dybdal 2003). Likewise, a novel ADC based on trastuzumab was evaluated in a dedicated NHP telemetry study to evaluate potential target-mediated CV effects (Poon et al. 2013). 

Fig. 25 Chemo-enzymatic conjugation of toxic drugs to homogeneous N-glycan of IgG-Fc for the development of efficacious antibody-drug conjugates (ADC). ...

---