Table II.
Mouse Model Parameters
Parameter | Definition | Unit | Value (CV%) | Source | |||
Binding | konCD3, koffCD3, Kd_CD3 | Binding of PF-06671008 to CD3 |
1/nM/h, 1/h nM |
1.72, 19.66 11.4 |
(7) | ||
konPcad, koffPcad, Kd_Pcad | Binding of PF-06671008 to P-cadherin |
1.57, 0.74 0.47 |
|||||
Central/peripheral compartment | V 1 | Volume of distribution in the central compartment | mL/kg | 49.6 (9) |
Estimated from mouse PK data. kel = CL/V1 k12 = CLd/V1 k21 = Cld/V2 |
||
V 2 | Volume of distribution in the peripheral compartment | mL/kg | 60.7 (16) | ||||
CL | Clearance | mL/h/kg | 0.45 (12) | ||||
CL d | Inter-compartmental clearance | mL/h/kg | 4.95 (28) | ||||
Omega CL | Inter individual variability in clearance | – | 0.064 (41) | ||||
a | Additive error | – | 0.067 (32) | ||||
b | Proportional error | – | 0.207 (15) | ||||
Tcells p 0 | Number of T cells administered/mouse | Cells/L | 0, 2.5e8, 5e8, 1e9, 1.25e9, 2.5e9 | See “Methods” section | |||
CD3 | CD3 expression on T cells | Receptors/cell | 100,000 | (17,18) | |||
Tumor disposition of PF-06671008/T cells | P | Permeability of drug into tumor | μm/day | 334 | (19) | ||
D | Diffusivity of drug into tumor | cm2/day | 0.022 | ||||
ε | Void fraction in tumor for drug | – | 0.24 | ||||
Rcap | Capillary radius | μm | 8 | ||||
Rkrogh | Average distance between 2 capillaries | μm | 75 | ||||
Tlag | Lag time for T cell disposition/onset of T cell proliferation in the tumor | Day | 5 | Set empirically, using in-house data | |||
kelT, k12T, k21T | T cell redistribution from the central compartment to the tumor | 1/day | 2.51, 0.002, 0.0005 | ||||
Tumor compartment | P rate | T cell proliferation rate | 1/h | Function of dose. Eq. (9) | See “Methods” section | ||
k _exhaust c | Slope of T cell decline | 1/h | 0.0412 | Interpolated from (20) | |||
Tumor cellst | Number of tumor cells | Cells/g of tumor | 1e8 | (21) | |||
mPcad | P-cadherin expression on tumor cells | Receptors/cell |
28,706 (HCT-116) 17,500 (SUM-149) |
(15) | |||
Rtumor | Tumor radius | cm | Calculated from w | Measured | |||
k int | P-cadherin internalization rate | Day−1 | 0.1728 (−) | Estimated from mouse tumor PK data. Represents 96 h half-life of internalization. | |||
Tumor growth inhibition | Mouse tumor models | HCT116 a | HCT116 b | SUM149 b | |||
k g0 | Exponential tumor growth rate | 1/day | 0.30 (−) | 0.19 (3) | 0.12 (3) | Estimated in mouse models from unperturbed tumor growth data | |
k g | Linear tumor growth rate | mm3/day | 105 (4) | 123 (2) | 74.3 (5) | ||
M max | Maximum tumor volume | mm3 | 3.8 × 103 (−) | 6.0 × 103 (−) | 5.8 × 103 (−) | ||
ψ | Switch between exponential and linear growth phases | – | 20 (−) | Fixed based on (22) | |||
k max | Maximum killing rate | 1/day | 0.74 (7) | 1.32 (7) | 2.71 (14) | Estimated in mouse models | |
kC 50 | Concentration at half maximum kill rate | nM | 1.0 × 10−4 (6) | 6.9 × 10−5 (7) | 2.0 × 10−4 (15) | ||
τ | Transduction time between tumor compartments | Day | 4.78 (10) | 3.99 (1) | 2.25 (3) | ||
Omega k g0 | Inter-individual variability in exponential growth rate | 0.46 (14) | 0.34 (11) | 0.12 (25) | |||
Omega k g | Inter-individual variability in linear growth rate | 0.35 (13) | 0.16 (13) | 0.16 (28) | |||
a | Additive error | 5 (−) | 60 (−) | 60 (−) | |||
b | Proportional error | 0.26 (3) | 0.06 (6) | 0.01(50) | |||
TSC (pM) (80% confidence interval) | Tumor static concentration of the trimer | 0.064 (0.044, 0.096) | 0.011 (0.0096, 0.013) | 0.0092 (0.0071, 0.012) |
aT cell engrafted tumor model
bT cell adoptive transfer tumor model
cOnset of exhaustion of T cells set to 7 days after disposition in the tumor
MWt of PF-06671008 = 105 kDa, MWt of sPcad = 85 kDa