On-Target Toxicity

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 

TABLE 3.1 General Differences between Biopharmaceuticals, Small-Molecule Pharmaceuticals, and ADCs 

Process Chemically derived Biologically derived Chemically and biologically derived 

Absorption, distribution, Distribution to many organs/tissues. Limited distribution. Catabolism/target-mediated 

Species specificity Typically species independent High species specificity High species specificity for on target species independent for off target  

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The dose escalation with overdose control (EWOC) is a Bayesian approach similar to CRM. It is a dose-escalation scheme based on controlling the probability of overdosing a patient and not on targetting toxicity between 20% and 30% of the MTD, as in the original CRM (41,42). This method, like CRM, sequentially modifies the dose-response curve by including the information of all the patients previously included in the trial, but in this case, the dose-effect relationship deals with a two-parameter model, which can be considered as a tolerance function between two bounds (d iin and dnmx) ... 

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. 

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