Figure 1.

Conceptual depiction of TENB2 receptor occupancy by anti-TENB2 ADC molecules, in the absence of antibody predosing, in low TENB2 expressing tissues (e.g. murine intestine) (A, C) and high TENB2 expressing tissues (e.g. tumor) (B, D). A very low ‘tracer’ dose (≤ 0.1 mg/kg) was employed in our previous studies to focus more on the intestinal antigen sink (A–B). In contrast, the present manuscript utilizes higher doses (≥ 1 mg/kg) that are relevant to efficacy (C–D). Three quantities must be considered when interpreting these tissue uptake values: 1) target concentration, which is low in intestine (A, C) and high in tumor (B, D), 2) absolute drug dose, which was low in the first study (A, B) and high in the current study (C, D), and 3) specific radioactivity of the administered drug solution, which, since total radioactivity is fixed across all studies to ensure appropriate gamma counting detection efficiency, was high in the first study (A, B) and low in the current study (C, D). As depicted qualitatively in panels A–D, these combinations of tissue-specific target concentrations, absolute drug doses and specific radioactivities across our studies resulted in unlabeled drug outcompeting radiolabeled drug for TENB2 binding in intestine but not in tumor when increasing total drug dose from tracer to therapeutic levels. Curved arrows indicate that unbound ADC molecules may exit the interstitial space and return to systemic circulation via lymphatic drainage.