Table 2.
Predicted human CL for total antibody analyte of ADCs using scaling from multiple nonclinical species
| ADCa , b | Observed CL (mL/day/kg) | Multiple species allometric scalinge | Maximum life potential as correction factore | Brain weight as correction factore | Rule of exponentsg | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mouse | Rat | Cyno | Human | x e | CLpred | PEf (%) | y e | CLpred | PEf (%) | z e | CLpred | PEf (%) | CLpred | PEf (%) | |
| DNIB0600Ac | 9.00 | ND | 13.3 | 12.2 | 1.08 | 16.7 | 36.6 | 1.49 | 15.6 | 27.7 | 2.08 | 15.0 | 22.9 | 14.99 | 22.9 |
| DMOT4039Ac | 9.50 | ND | 27.6 | 20.0 | 1.21 | 51.3 | 156 | 1.62 | 47.9 | 140 | 2.21 | 46.1 | 131 | 46.11 | 131 |
| Polatuzumab vedotinc | 5.09 | ND | 6.00 | 14.5 | 1.03 | 6.6 | −119 | 1.44 | 6.19 | −134 | 2.03 | 5.95 | −144 | 5.95 | −144 |
| Pinatuzumab vedotinc | 6.10 | ND | 9.40 | 13.8 | 1.08 | 12.1 | −14.1 | 1.50 | 11.3 | −22.0 | 2.08 | 10.9 | −26.8 | 10.88 | −26.8 |
| DSTP3086S | 9.90 | 9.50 | 13.4 | 8.20 | 1.06 | 15.0 | 83.4 | 1.47 | 11.7 | 42.6 | 2.06 | 10.1 | 23.4 | 10.12 | 23.4 |
| ADC1c | 6.60 | ND | 10.5 | 10.8 | 1.09 | 13.8 | 27.3 | 1.50 | 12.9 | 19.1 | 2.09 | 12.4 | 14.6 | 12.38 | 14.6 |
| T‐DM1 | 8.00 | 6.5 | 4.60 | 4.90 | 0.89 | 3.36 | −45.8 | 1.30 | 2.61 | −87.7 | 1.89 | 2.26 | −117 | 3.36 | −45.8 |
| Brentuximab vedotind | ND | 9.00 | 14.6 | 10.6 | 1.18 | 25.4 | 139 | 1.82 | 45.9 | 333 | 2.53 | 64.5 | 509 | 64.5 | 509 |
| APE | 77.7 | 101 | 124 | 115 | |||||||||||
| RSS | 1,337 | 2,136 | 3,693 | 2,908 | |||||||||||
ADC, antibody–drug conjugate; APE, average absolute value of percentage prediction error (|PE|); BrW, brain weight; BW, body weight; CL, clearance; cyno, cynomolgus monkeys; MPL, maximum life‐span potential; ND, no data; PK, pharmacokinetic; ROE, rule of exponent; RSS, residual sum of square.
aAll ADCs except for brentuximab vedotin are humanized immunoglobulin‐G1 (IgG1) antibodies. Brentuximab vedotin is a chimeric IgG1 antibody. bUse reported body weight for mice (20 g), rats (250 g), cyno (3.5 kg), and humans (70 kg). cOnly mice and cynomolgus monkey PK data are available. Regression was done based on two species. dOnly rat and cyno PK data are available. Regression was done based on two species. eMultiple species allometric scaling: CL = a · BWx; allometric scaling with MLP as correction factor: MLP · CL = b · BWy; allometric scaling with BrW as correction factor: BrW · CL = c · BWz; where a, b, and c is the coefficient and x, y, and z is the exponent of the allometric equation. fPEs = ((CLhuman, predicted − CLhuman, observed)/CLhuman, observed) × 100% for overprediction and ((CLhuman, predicted − CLhuman, observed)/CLhuman, predicted) × 100% for underprediction. gROE proposed by Mahmood12 for monoclonal antibodies: according to ROE, MLP as a correction factor was used when exponents of simple allometry are <0.71, whereas BrW correction was used when exponents of simple allometry are > 1.