Why Knowledge of Translational PK/PD at Sites of Action Are Important to Optimize Bispecific Antibody Development?

Transcription

1 Why Knowledge of Translational PK/PD at Sites of Action Are Important to Optimize Bispecific Antibody Development? Weirong Wang, Ph.D. Biologics Clinical Pharmacology

2 Why Knowledge of Translational PK/PD at Sites of Action Are Important to Optimize Bispecific Antibody Development?

3 Translational PK/PD 3

4 Mechanistic PK/PD Model in the Translational Space Mechanistic PK/PD model describes the PK/PD relationship in a biologically realistic manner The objective is not to simply describe the data, but to correlate drug PK and PD with its mechanism of action Distinguishes drug and system specific parameters to improve predictive power and allow extrapolation 4

5 Blinatumomab: bi-specific T- engagers (BiTEs) for relapsed or refractory acute lymphoblastic leukemia (ALL) Kapoor A, et al. (2014) Clin Cancer Investig J;3:

6 Dissect the Mechanism of Action for T Cell Redirecting Agents + Target + Tumor Receptor occupancy-based target killing T k on2 k off2 + Target T The killing of target s is driven by formation of target-bite-t complexes k on1 k off1 k on1 k off1 T T k g Target T + k on2 k off2 Target Target k el 6

7 % lysis Modeling the Blinatumomab Data in Literature The binding/killing model was used to analyze the reported cytotoxicity data of blinatumomab K D CD3: 1E-7 M K D CD19: 1E-9 M + Target + Tumor T k on2 k off2 + Target T k on1 k off1 k on1 k off1 T T k g Target + T k on2 k off2 Target Target k el conc Mølhøj M, et al. (2007) Mol Immunol. 44: Emax : 85.8 Base: 0 EC50: Gamma: 5 K g(tm) : K el(tm)-max :

8 Use the Mechanism-based Model for In Vitro In Vivo Extrapolation What has changed? T density Cell surface target density Drug conc (PK) Simulated blinatumomab cytotoxicity profile in patients What (we assume) has not changed? The cytotoxicity is driven by formation of the triple complex Actual steady state conc determined in clinics The potency constant EC 50 The K D (k on, k off ) The targeted Css of blinatumomab in clinics is close to the model-predicted maximum % cytotoxicity 8

9 Site-of-Action For biologics against tissue targets, the PK/PD relationship in blood does not necessarily reflect what happens at the tissue site Distribution Target-mediated drug disposition (TMDD) Some biologics, e.g. bi-specific Abs, are designed to modulate tissue distribution Physiologically-based PK/PD modeling is often required to characterize the tissue effect Requires large amount of data to support the model 9

10 Team Wants to Develop a Bispecific Agent for RA Using Joint Targeting... Which bispecific platform should we choose? Systemic PK vs tissue distribution What are desired affinities to the anchor and to the therapeutic target? Spiess C, et al. (2015) Mol Immun;67:

11 Lymph Blood Minimal Physiologically-Based Pharmacokinetic (mpbpk) Model (1-σ L )*L1 Tight Tissues (1-σ1)*L1 (1-σ L )*L2 Leaky Tissues (1-σ2)*L2 (1-σ L )*L3 Tissue of Interest (1-σ3)*L3 σ: Reflection coefficient L: Lymph flow Provides a modeling platform to assess drug action at tissue site Maintained the concept of a full PBPK model, e.g. parameters with physiological and anatomical meanings Flexibility to incorporate tissue compartments of interest Feasibility to implement TMDD kinetics in both systemic and tissue compartments Cao Y, Jusko WJ (2014) J PKPD 41:

12 mpbpk Model for a mab against IL-6 in Mice with Collagen-Induced Arthritis (CIA) Objective To understand the distribution of CNTO 345, an anti-mil-6 mab, to tissue site (ankle joint) and its ability to neutralize IL-6 at the joint Data collected 3 dose levels PK, total IL-6 and free IL-6 in both serum and joint lavage A mpbpk model incorporated target binding in both systemic and site of action (joint) was successfully developed Dilution effect 12

13 Impact of CIA on mab Disposition Serum Lavage/serum ratio Joint Lavage 13

14 Compare PK and Free/Total IL-6 Profiles in Serum and Joint Lavage The interrelationships of CNTO 345 and IL-6 in serum and joints differ greatly Minimal accumulation of total IL-6 in the joint lavage Efficient lowering of free IL-6 at the joint 30mg/kg 3mg/kg 14

15 Stepwise Development of a mpbpk model for CNTO 345 in CIA Mice 1 2 Systemic PK Systemic TMDD Data: Serum mab PK Data: Serum total/free IL Tissue PK Tissue TMDD Data: Joint mab PK Data: Joint total/free IL-6 15

16 Model Structure K ss = k off + k int k on σ: Reflection coefficient Biotechnology Center of Exence 16

17 Model Fitting: Serum Biotechnology Center of Exence 17

18 Model Fitting: Joint Lavage Biotechnology Center of Exence 18

19 Joint Serum Parameter Definition Estimate RSE(%) σ 1 σ 2_CIA CL CIA (ml/day) V max (pmol/day) Vascular reflection coefficient of tight tissue Vascular reflection coefficient of leaky tissue Linear serum clearance in CIA mice 0.98 Fixed Capacity constant K m (nm) Affinity constant k deg (1/day) k int (1/day) K ss (pmol/ml) IL-6 serum (pmol/ml) σ joint Degradation rate constant of IL-6 in serum Elimination rate constant of mab-il-6 complex Quasi-equilibrium binding constant Baseline concentration of serum IL-6 Vascular reflection coefficient L joint (ml/day) Lymphatic flow rate k deg_j (1/day) k int_j (1/day) K ss_j (pmol/ml) IL-6 bl_joint (pmol/ml) Degradation rate constant of IL-6 Elimination rate constant of the mab- IL-6 complex Quasi-equilibrium binding constant Baseline concentration of IL Serum Joint Modeling Results Typical mab PK Rapid elimination of free IL-6 Elimination of complex >100-fold slower than free IL-6 Estimated Kss similar to in vitro K D Vascular permeability of joint between tight and leaky tissues ~100-fold higher IL-6 baseline Elimination of mab and complex driven by lymph flow >10-fold slower elimination of free IL-6 than in serum, ~2.5x of lymph flow Kss in joint higher than Kss in serum, mostly due to higher faster elimination of complex Biotechnology Center of Exence 19

20 Lessons Learned Free cytokine suppression at tissue sites cannot be simply extrapolated from data in serum Limited tissue distribution of the drug Differences in the target baseline Differences in the elimination rates between drug, free target and drug/target complex However, with sufficient mechanistic understanding, it is possible to predict the cytokine suppression at the tissue site based on information collected from systemic circulation Factors governing the tissue distribution of biologics are mostly physiological processes 20

21 Which bispecific platform should we choose? Systemic PK vs tissue distribution What are desired affinities to the anchor and to the therapeutic target? Spiess C, et al. (2015) Mol Immun;67:

22 Local drug conc (nm) Select a Bispecific Ab Platform for Joint Targeting Modeling and simulation results provided guidance on the factors that will have bigger impact on drug concentrations at the joint Systemic t 1/2 Tissue distribution Expression level Affinity Long Medium Short Low Medium High Without EDB Without EDA/B 2.5 nm 25 nm 100 nm 250 nm Without EDA/B Low Medium High 22

23 I often say that when you can measure what you are speaking about, and express it in numbers, you know something about it; but when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind. -- Lord Kelvin (Baron William Thomson Kelvin), Malcolm Rowland, ASCPT

24 Acknowledgements Xi (Cindy) Chen Xiling Jiang Lanyi Xie Tom McIntosh Rajitha Doddareddy Elayne Dell Honghui Zhou... Biologics Clinical Pharmacology 24

25 Thank You