Prediction of Human Pharmacokinetics and Clinical Effective Dose of SI–B001, an EGFR/HER3 Bi-specific Monoclonal Antibody

Recent Advances in Translational Pharmacokinetics and Pharmacodynamics Prediction of Therapeutic Antibodies Using Modeling and Simulation

“…This approach assumes a comparable exposure–anti-tumor activity relationship between the humans and xenograft mouse model. A similar tumor-growth-inhibition-model-based approach has been reported for PRO95780 (anti-DR5 antibody) [ 70 ], rhuMAb VEGF (anti-VEGF antibody) [ 71 ], SI-B001 (anti-EGFR/HER3 bispecific antibody) [ 67 ], and MCLA-128 (anti-HER2/HER3 bispecific antibody). Since the mechanistic process is not incorporated into this model, it cannot account for the mechanism-based inter-species differences in effective concentration.…”

“…Although plasma mAbs concentration–time profiles in humans at high concentrations were reasonably predicted, those at low concentrations were poorly predicted, suggesting the need to further improve the scaling methodology. The MM-model-based approach has been applied to several mAbs such as E6011 (anti-CX3CL1 antibody) [ 65 ], MCLA-128 (anti-HER2/HER3 bispecific antibody) [ 66 ], and SI-B001 (anti-EGFR/HER3 bispecific antibody) [ 67 ]. Recently, Singh et al investigated the utility of three approaches (species time-invariant method, MM model, and minimal physiologically based pharmacokinetics (mPBPK) model) to predict the nonlinear pharmacokinetics of mAbs in humans from cynomolgus monkey data using five mAbs [ 68 ].…”

Preclinical Characterization of ASP2713, a Novel Igβ and FcγRIIB Cross-Linking Antibody, for Prediction of Human Pharmacokinetics and Clinically Effective Dose

“…Second, regarding the allometric scaling exponent for V max , although V max is the maximum non-linear component of elimination clearance velocity that relates to total target concentration profile, 12 no information is available about a possible species difference between monkeys and humans in the amount of Igb of BCR on whole blood B cells. It has been reported that values from 0.75 to 1 were used for the allometric scaling exponent of V max ; [13][14][15][16][17] however, to avoid underestimation of the clinically effective dose, we assumed that V max in humans was the same as that in cynomolgus monkeys in the present study.…”

HER3 in cancer: from the bench to the bedside

“…This bispecific tetravalent antibody is based in the model of an IgG-(scFv)2 structure that consists of a complete IgG with two heavy and two light chains, and two scFv components connected to either C or N terminals of the heavy or light chains [207]. SI-B001 has recently demonstrated its efficacy in colon, HNSCC and esophageal cancer xenograft models, achieving almost complete inhibition of the growth in the last two models [208]. SI-B001 is now being tested in phase I and II clinical trials.…”