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. 2019 May 22;21(4):66. doi: 10.1208/s12248-019-0332-z

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