Hazard characterization of an anti-human tissue factor antibody by combining results of tissue cross-reactivity studies and distribution of hemorrhagic lesions in monkey toxicity studies.

Tissue cross-reactivity (TCR) studies are conducted when developing therapeutic antibodies, but their value is sometimes questioned because the positive organs often do not match the target organs of toxicity. We conducted TCR studies in human and cynomolgus monkey tissues for the development of an anti-human tissue factor antibody (TFAb) and also for a commercially available antibody, to clarify the true distribution of the target antigen. Tissue factor (TF) was found to be distributed in a wide variety of organs and tissues, including the heart and urinary bladder, in human and monkey. Administration of the TFAb to cynomolgus monkey caused hemorrhagic lesions mainly in the heart and urinary bladder in an incidental manner. This was thought to show the physiological role of TF in regulating hemostasis in these organs. Because the distribution of antigen in human and monkey was similar, the possibility that the TFAb would have similar effects in human was judged to be high, and because of the incidental nature of the effects, that they would be difficult to avoid. Thus it was possible to prospectively characterize the hazardous potential of a therapeutic antibody by accurately evaluating the tissue distribution of the target antigen and understanding its biological nature.