On translation of antibody drug conjugates efficacy from mouse experimental tumors to the clinic: a PK/PD approach.
Objectives of the present investigation were: (1) to compare three literature reported tumor growth inhibition (TGI) pharmacodynamic (PD) models and propose an optimal new model that best describes the xenograft TGI data for antibody drug conjugates (ADC), (2) to translate efficacy of the ADC Trastuzumab-emtansine (T-DM1) from mice to patients using the optimized PD model, and (3) to apply the translational strategy to predict clinically efficacious concentrations of a novel in-house anti-5T4 ADC, A1mcMMAF. First, the performance of all four of the PD models (i.e. 3 literature reported + 1 proposed) was evaluated using TGI data of T-DM1 obtained from four different xenografts. Based on the estimates of the pharmacodynamic/pharmacokinetic (PK/PD) modeling, a secondary parameter representing the efficacy index of the drug was calculated, which is termed as the tumor static concentration (TSC). TSC values derived from all four of the models were compared with each other, and with literature reported values, to assess the performance of these models. Subsequently, using the optimized PK/PD model, PD parameters obtained from different cell lines, human PK, and the proposed translational strategy, clinically efficacious doses of T-DM1 were projected. The accuracy of projected efficacious dose range for T-DM1 was verified by comparison with the clinical doses. Aforementioned strategy was then applied to A1mcMMAF for projecting its efficacious concentrations in clinic. TSC values for A1mcMMAF, obtained by fitting TGI data from 4 different xenografts with the proposed PK/PD model, were estimated to range from 0.6 to 11.5 μg mL⁻¹. Accordingly, the clinically efficacious doses for A1mcMMAF were projected retrospectively. All in all, the improved PD model and proposed translational strategy presented here suggest that appropriate correction for the clinical exposure and employing the TSC criterion can help translate mouse TGI data to predict first in human doses of ADCs.
Department of Pharmacokinetics Dynamics and Metabolism, Translational Research Group, Pfizer Global Research and Development, Groton, CT, 06340, USA, nahor.haddish-berhane@pfizer.com.
Nahor
N
Haddish-Berhane
Dhaval K
DK
Shah
Dangshe
D
Ma
Mauricio
M
Leal
Hans-Peter
HP
Gerber
Puja
P
Sapra
Hugh A
HA
Barton
Alison M
AM
Betts
D000080044:Ado-Trastuzumab Emtansine; D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008453:Maytansine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000906:Antibodies; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D008453:Maytansine; D000068878:Trastuzumab; D000080044:Ado-Trastuzumab Emtansine