Table 2.
Human in vitro and cynomolgus monkey in vivo data used for the in vitro-in vivo correlation
|
In vivo data |
In vitro data | |||||
|---|---|---|---|---|---|---|
| Tested antibody | Description | Dose (mg/kg) | Terminal half life (h) | Total CL (mL/day/kg) | Number of animals | Wt IgG-normalizedin vitro fluxpH 6.0/7.4 |
| mAb 1 | hu IgG1, AAA mutant; FcRn non-binder | 0.3 | 53 | 16.1 | 2 | 0.31 ± 0.01 |
| mAb 2 | hu IgG1, FcRn Wt binder | 0.3 | 79 | 6.49 | 2 | 1.00 ± 0.09 |
| mAb 3 | hz IgG1, FcRn Wt binder | 10 | 310 ± 57 | 3.12 ± 0.55 | 4 | 1.64 ± 0.23 |
| mAb 4 | hu IgG1, FcRn Wt binder | 75 | 269 | 5.23 | 2 | 0.97 ± 0.07 |
| mAb 5 | hu IgG1, FcRn Wt binder | 0.3 | 108 | 3.84 | 2 | 0.63 ± 0.09 |
| mAb 6 | hu IgG1, AAA; FcRn non-binder | 0.3 | 32 | 15.4 | 2 | 0.25 ± 0.01 |
| mAb 7 | hu IgG1, FcRn Wt binder with FcRn-unrelated CL component | 1 | 178 | 24.7* | 3 | 0.84 ± 0.1 |
| mAb 8 | chimeric IgG (hu Fc), FcRn Wt binder | 5 | NC* | 3.60* | 2 | 0.91 ± 0.1 |
| mAb 9 | chimeric IgG (hu Fc), FcRn Wt binder | 0.8 | 380 ± 89 | 2.46 ± 0.35 | 3 | 0.95 ± 0.18 |
| mAb 10 | hu IgG1, enhanced FcRn-binding; positive charge patches | 20 | 288 | 2.86 | 2 | 4.14 ± 0.82 |
| mAb 11 | hz IgG1, FcRn Wt binder (bevacizumab, Avastin) | 5 | Deng et al20 | 3.97 | Deng et al20 | 0.83 ± 0.07 |
| mAb 12 | hu IgG1, FcRn Wt binder | 20 | 235 ± 156 | 4.52 ± 1.07 | 3 | 1.27 ± 0.1 |
| mAb 13 | hu IgG1, enhanced FcRn-binding | 20 | 137 ± 73 | 3.51 ± 0.8 | 3 | 3.42 ± 0.15 |
| mAb 14 | hz IgG1, FcRn Wt binder (trastuzumab, Herceptin) | 5 | Deng et al20 | 5.52 | Deng et al20 | 1.77 ± 0.03 |
| mAb 15 | hu IgG4, FcRn Wt binder | 2.5 | 355 ± 34 | 2.56 ± 0.33 | 3 | 1.10 ± 0.2 |
| mAb 16 | hu IgG1, FcRn Wt binder | 10 | 59 | 9.81 | 2 | 1.03 ± 0.09 |
| mAb 17 | hz IgG1, FcRn Wt binder | 10 | 194 | 5.88 | 2 | 1.06 ± 0.05 |
| mAb 18 | hz IgG1, FcRn Wt binder | 0.15, 1.5, 15, 150 | 150* | 5.86* | 8 | 1.41 ± 0.06 |
| mAb 19 | hu IgG1, FcRn Wt binder | 100 | 282 | 4.49 | 2 | 1.49 ± 0.26 |
| mAb 20 | hz IgG1, FcRn Wt binder | 50 | NC* | 3.34* | 3 | 2.13 ± 0.35 |
| mAb 21 | hu IgG1, FcRn Wt binder | 1 | 218 ± 74.6 | 3.74 ± 0.32 | 4 | 1.07 ± 0.34 |
| mAb 22 | hz IgG1, FcRn Wt binder | 30 | 240 | 4.61 | 2 | 0.95 ± 0.07 |
| mAb 23 | hz IgG1, FcRn Wt binder | 30 | 94.2 | 3.57 | 2 | 1.11 ± 0.16 |
| mAb 24 | hu IgG1, FcRn Wt binder | 150 | 242 | 8.16* | 6 | 2.75 ± 0.19 |
*
PK parameters estimated by population approach, no SD applicable
mAb systemic clearance from non- compartmental (NCA) PK analysis and terminal half-life after intra-venous dose to monkeys is reported together with the respective mAb wt-normalized Papp from human cellular FcRn assay (pH 6.0/7.4). Data are given as mean values ± standard deviation in case of > 2 subjects or measurements.
hu: human; hz: humanized; Wt: wildtype mAb without mutations of the FcRn-binding sites; TMDD: target-mediated drug disposition.