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. Author manuscript; available in PMC: 2021 Jul 1.
Published in final edited form as: Mol Cancer Ther. 2020 Nov 11;20(1):203–212. doi: 10.1158/1535-7163.MCT-20-0451

Fig. 3. Impact of target expression in normal tissue – target mediated drug disposition (TMDD).

Fig. 3.

Using a cross-reactive antibody that binds both human (in the tumor xenograft) and mouse (endogenous FR in multiple tissues) receptor, the ADC at the same dose showed significantly increased plasma clearance (A) because of binding FR in normal tissues. The faster clearance reduced tumor exposure, resulting in lower payload levels within the tumor (B). While a 2.5 mg/kg dose of the non-cross-reactive DM4-ADC (M-s-SPDB-DM4) results in complete responses in a high expression KB xenograft mouse system(14), the faster clearance and lower tumor uptake of the cross-reactive DM4-ADC (rmFR1–12-s-SPDB-DM4) contributes to the decreased efficacy (C). Note M-s-SPDB-DM4 data is replotted from Fig. 1 for comparison purposes. Between 6 and 10 mg/kg doses are needed for complete responses with the cross-reactive ADC (Fig. S4 and Fig. S5).