PT  - JOURNAL ARTICLE
AU  - Frans V. Suurs
AU  - Grit Lorenczewski
AU  - Julie M. Bailis
AU  - Sabine Stienen
AU  - Matthias Friedrich
AU  - Fei Lee
AU  - Bert van der Vegt
AU  - Elisabeth G.E. de Vries
AU  - Derk Jan A. de Groot
AU  - Marjolijn N. Lub-de Hooge
TI  - Mesothelin/CD3 Half-Life–Extended Bispecific T-Cell Engager Molecule Shows Specific Tumor Uptake and Distributes to Mesothelin and CD3-Expressing Tissues
AID  - 10.2967/jnumed.120.259036
DP  - 2021 Dec 01
TA  - Journal of Nuclear Medicine
PG  - 1797--1804
VI  - 62
IP  - 12
4099  - http://jnm.snmjournals.org/content/62/12/1797.short
4100  - http://jnm.snmjournals.org/content/62/12/1797.full
SO  - J Nucl Med2021 Dec 01; 62
AB  - Bispecific T-cell engager (BiTE) molecules exert antitumor activity by binding one arm to CD3 on cytotoxic T cells and the other arm to a tumor-associated antigen. Methods: We generated a fully mouse cross-reactive mesothelin-targeted BiTE molecule that is genetically fused to an Fc-domain for half-life extension, and we evaluated the biodistribution and tumor targeting of a 89Zr-labeled mesothelin half-life–extended (HLE) molecule in 4T1 breast cancer–bearing syngeneic mice with PET. The biodistribution of 50 μg of 89Zr-mesothelin HLE BiTE was studied over time by PET imaging in BALB/c mice and revealed uptake in tumor and lymphoid tissues with an elimination half-life of 63.4 h. Results: Compared with a nontargeting 89Zr-control HLE BiTE, the 89Zr-mesothelin HLE BiTE showed a 2-fold higher tumor uptake and higher uptake in lymphoid tissues. Uptake in the tumor colocalized with mesothelin expression, whereas uptake in the spleen colocalized with CD3 expression. Evaluation of the effect of protein doses on the biodistribution and tumor targeting of 89Zr-mesothelin HLE BiTE revealed for all dose groups that uptake in the spleen was faster than in the tumor (day 1 vs. day 5). The lowest dose, 10 μg, of 89Zr-mesothelin HLE BiTE had higher spleen uptake and faster blood clearance than the higher doses, 50 and 200 μg. 89Zr-mesothelin HLE BiTE tumor uptake was similar at all doses. Conclusion: The mesothelin HLE BiTE showed specific tumor uptake, and both arms contributed to the biodistribution profile. These findings support the potential for clinical translation of HLE BiTE molecules.