Interspecies Scaling of Therapeutic Monoclonal Antibodies: Initial Look

Abstract

The authors evaluated interspecies scaling for the prediction of human clearance of 18 therapeutic monoclonal antibodies (mAbs). Human and monkey/chimpanzee data of 14 mAbs were classified based on the targeted antigens (soluble or membrane bound). Simple allometry and/or a time-invariant method (elementary Dedrick plot) were performed. Results indicate that human clearance might be accurately predicted from monkey data for mAbs targeting soluble receptors or membrane-bound receptors with limited tissue distribution using simplified allometry. The optimal exponents were estimated to be 0.85 or 0.90. If nonlinearity is anticipated at the human efficacious dose, pharmacokinetic parameters obtained at high doses in animals might not be sufficient for full pharmacokinetic characterization and prediction. Using prespecified criteria, including predicted human clearance (< or = or > 10 mL/d/kg), simplified allometric scaling might be helpful in predicting the effect of receptor-mediated clearance for mAbs targeting membrane-bound antigens. Furthermore, simplified allometry and an elementary Dedrick plot provide similar results in predicted clearance. Given the significant advantages offered by simplified allometry, it should be used when data are available from only 1 species. When reasonable data from > or =3 species are available, traditional allometry should be explored. Overall, clearance prediction is useful for human dose prediction in drug discovery and development.

Mechanistic Investigation of the Preclinical Pharmacokinetics and Interspecies Scaling of PF-05231023, a Fibroblast Growth Factor 21–Antibody Protein Conjugate

“…A fixed exponent of 0.80 was previously shown to be an appropriate singlespecies scaling factor for predicting human CL for a wide variety of therapeutic proteins and mAbs (Wang and Prueksaritanont, 2010). Other studies based on an overlapping data set of therapeutic mAbs supported use of a fixed exponent ranging from 0.75 to 0.90 to predict human CL from monkey (Ling et al, 2009;Deng et al, 2011;Dong et al, 2011;Oitate et al, 2011Oitate et al, , 2012. The range of exponents reported for mAbs is not surprising, given the relative insensitivity of this parameter toward single-species scaling between monkeys and humans (e.g., an exponent between 0.67 and 0.90 results in an approximately 2-fold change in predicted human CL).…”

Linear pharmacokinetic parameters for monoclonal antibodies are similar within a species and across different pharmacological targets: A comparison between human, cynomolgus monkey and hFcRn Tg32 transgenic mouse using a population-modeling approach

“…Their study of 14 mAbs indicated that, for mAbs with linear kinetics, CL in humans could be reasonably predicted from monkey data using simplified allometry with a fixed exponent. The optimal exponents were estimated to be 0.85 for soluble antigens and 0.9 for membrane-based antigens 13 . In a similar analysis of 13 mAbs with linear CL, Deng et al showed that simple allometric scaling of CL in cynomolgus monkey with an exponent of 0.85 provided a good estimate of human CL 11 .…”

Quantitative Prediction of Human Pharmacokinetics for mAbs Exhibiting Target-Mediated Disposition

“…mAb-1 (Efalizumab) Chimpanzees 6.11 (25) 0.427 (12) 0.123 (11) 2.92 (11) 0.395 (24) 0.383 (8) 3.17 (9) 0.303 (8) Patients 5.41 (13) 0.516 (21) 0.112 (11) 4.47 (9) 0.286 (18) 0.506 (11) 2.06 (9) 0.597 (6) mAb-2 (TRX-1) Baboons 32.4 (27) 398 (75) 2.04 (69) 0.931 (17) 0.84 (106) 4.57 (143) 2.04 (69)…”

“…Healthy volunteers 28.4 (24) 30.1 (15) 4.25 (12) 3.79 (11) 0.14 (100) 0.413 (85) 4.25 (12) 0.867 (14) mAb-3 (MTRX-1011A) 0.109 (7) 2.85 (16) 0.549 (13) 1.35 (21) 5.17 (4) 1.35 (2) mAb-4…”

“…approaches; i.e., simple allometry, allometry with brain weight correction, and fixed exponent method. Similarly, Ling et al performed an analysis of 14 mAbs where clearance was scaled from nonhuman primates as preclinical species using fixed exponent method (12). Deng et al have also showed recently that simple allometry of monkey CL alone with an exponent of 0.85 provided a preferable prediction of human clearance (13).…”