Pharmacokinetics and dosimetry of radiolabeled FAP-targeting single-domain antibody 4AH29 in Göttingen minipigs

Background Fibroblast activation protein alpha (FAP) is a pan-tumor target highly expressed on cancer-associated fibroblasts. We developed 4AH29, a single-domain antibody binding FAP, and investigated the biodistribution of [ 131 I]I-GMIB-4AH29 and [ 111 In]In-DOTA-4AH29 in Göttingen minipigs. Methods Following radiopharmaceutical administration, blood activity profile was determined by gamma-counter and biodistribution kinetics were determined using gamma-counter measurements and SPECT/CT imaging, respectively. The data obtained with [ 111 In]In-DOTA-4AH29 were used as a surrogate for its 177 Lu- and 225 Ac-labeled analogues and extrapolation to human absorbed dose was calculated for all analogues. Results Radiolabeled 4AH29 showed good tolerability within the studied time frame. It displayed fast blood clearance driven by renal excretion. Kidney clearance dynamics of [ 131 I]I-GMIB-4AH29 and [ 111 In]In-DOTA-4AH29 were distinct, likely driven by the different radiolabeling chemistry for halogen or metal conjugation. However, the contrasting patterns did not translate into relevant differences in mean residence time (MRT), nor was there a significant difference in bone marrow or liver MRTs when comparing halogen and metal-radiolabeled 4AH29. Extrapolated human absorbed doses for [ 131 I]I-GMIB-4AH29 and [ 177 Lu]Lu-DOTA-4AH29 were compared given their similar particle decay and comparable physical half-lives. In kidneys, [ 131 I]I-GMIB-4AH29 led to an extrapolated human absorbed dose of 8.23E-01 mGy/MBq, whereas [ 177 Lu]Lu-DOTA-4AH29 reached 5.86E-01 mGy/MBq. Consequently, the maximum tolerable administered activities were 28 and 39 GBq, respectively, to reach the renal absorbed dose limit of 23 Gy as determined by external beam radiation therapy (EBRT). In red marrow, the equivalent dose for [ 131 I]I-GMIB-4AH29 was 3.8E-02 mGy/MBq and 1.36E-02 mGy/MBq with [ 177 Lu]Lu-DOTA-4AH29. Thus, 53 GBq and 148 GBq can be administered, respectively, before reaching the EBRT set absorbed dose threshold of 2 Gy. Conclusion 4AH29 radiolabeled with 131 I or 111 In is well tolerated in Göttingen minipigs within the studied time frame. Extrapolated dosimetry of radiolabeled 4AH29 using OLINDA software indicates that its administration within a clinically relevant range is possible without exceeding toxicity limits in critical organs.