Journal: Journal of Pain Research

Article Title: Neuropathic pain and cytokines: current perspectives

doi: 10.2147/JPR.S53660

Figure Lengend Snippet: Schematic representation of spinal cytokine/chemokine signaling mechanisms which contribute to enhanced nociceptive transmission following peripheral nerve injury. Notes: Primary afferent fibers (Aβ [blue], Aδ [green] and C [red]) transmit signals from the periphery, through the DRG to the dorsal horn of the spinal cord. Following damage to a peripheral nerve, a number of cytokine/chemokine signaling systems exhibit plastic changes at the first synapse in the pain pathway. Abbreviations: Aβ, A beta fiber; Aδ, A delta fiber; DRG, dorsal root ganglia; JAK/STAT, Janus kinase/signal transducer and activator of transcription; IL, interleukin; NMDA, N-methyl-D-aspartate; CCL2, chemokine ligand 2; TNF, tumor necrosis factor; NFκB, nuclear factor kappa B; TNFR, tumor necrosis factor receptor; CX3CR1, CX3C chemokine receptor 1; CX3CL1, CX3C chemokine ligand 1; CatS, cathepsin S; CCR2, chemokine receptor type 2; R, receptor; JNK, c-Jun N-terminal kinase; ERK, extracellular signal-regulated kinase; p38, p38 mitogen-activated protein kinase.

Article Snippet: Disappointingly, a recent clinical trial by AstraZeneca failed to demonstrate efficacy of a systemically administered CCR2 antagonist in patients with posttraumatic neuralgia.

Techniques: Transmission Assay

Journal: Clinical and Translational Science

Article Title: Population‐Based Modeling to Predict Human PK / PD of TAK ‐500, an Anti‐CCR2 Antibody–Drug Conjugate for First‐in‐Human Study in Cancer Patients

doi: 10.1111/cts.70522

Figure Lengend Snippet: Overlay between TAK‐202 simulations and observed TAK‐500 total antibody profiles in cynomolgus monkeys. (A) Observed serum concentration of the parental CCR2 antibody (TAK‐202) in cynomolgus monkeys post intravenous bolus administration. (B) The model structure represents the population PK model of the parental antibody (TAK‐202). (C–E) The plots represent the overlay between the TAK‐202 simulation and the observed TAK‐500 total antibody profiles. The TAK‐202 prediction interval (95% PI) was computed from 1000 simulations. Ac, estimated amount of TAK‐202 in the central compartment; At, model estimated amount of TAK‐202 in the peripheral compartment; Cp, plasma concentration of TAK‐202; IV, intravenous; kel, central compartmental elimination rate constant; Km, drug concentration at 50% of maximal elimination rate; kpt, distribution rate constant from plasma to tissue; ktp, distribution rate constant from tissue to plasma; Vc, central volume of distribution; V max , maximal elimination rate; Vt, peripheral volume of distribution.

Article Snippet: Murine antihuman CCR2 mAb (Mu1D9), humanized anti‐hCCR2 monoclonal antibody (TAK‐202), a mouse anti‐TAK‐202 idiotypic antibody, and TAK‐500, a TAK‐202‐derivative iADC conjugated to an interferon pathway agonist payload TAK‐676, were generated at Takeda Pharmaceuticals International Inc. (Cambridge, MA, USA).

Techniques: Concentration Assay, Clinical Proteomics

Journal: Clinical and Translational Science

Article Title: Population‐Based Modeling to Predict Human PK / PD of TAK ‐500, an Anti‐CCR2 Antibody–Drug Conjugate for First‐in‐Human Study in Cancer Patients

doi: 10.1111/cts.70522

Figure Lengend Snippet: TAK‐202 population PK‐RO model in human. (A) Observed serum concentration of the parental CCR2 antibody (TAK‐202) in human post intravenous administration. (B) The model structure represents the population PK‐RO model of the parental antibody (TAK‐202) linking the PK profiles with the CCR2 receptor occupancy on classical monocytes. (C–H) The plots represent overlay of observed versus model predicted PK profile in human population when administered intravenously for 1 h with TAK‐202, dosed at 0.1, 0.3, 1, 3, 6, 10 mg/kg. (I–N) The plots represent overlay of observed vs. model predicted unbound CCR2 receptors on the surface of monocytes in human population when administered with TAK‐202, dosed at 0.1, 0.3, 1, 3, 6, 10 mg/kg, given intravenously for 1 h. Prediction intervals (95% PI) are calculated from 1000 simulations. Ac, estimated amount of TAK‐202 in the central compartment; At, model estimated amount of TAK‐202 in the peripheral compartment; Cp, plasma concentration of TAK‐202; E max , maximal receptor occupancy; IC 50 , concentration of anti‐CCR2 antibody driving 50% of receptor occupancy; IV, intravenous(ly); kel, central compartmental elimination rate constant; kin, rate constant representing the distribution of monocytes from plasma to tissue; Km, drug concentration at 50% of maximal elimination rate; kout, rate constant representing the distribution of monocytes from tissue to plasma; kpt, distribution rate constant from plasma to tissue; ktp, distribution rate constant from tissue to plasma; MESF, molecules of equivalent soluble fluorophore; RO 0 , baseline receptor occupancy; Vc, central volume of distribution; V max , maximal elimination rate; Vt, peripheral volume of distribution.

Article Snippet: Murine antihuman CCR2 mAb (Mu1D9), humanized anti‐hCCR2 monoclonal antibody (TAK‐202), a mouse anti‐TAK‐202 idiotypic antibody, and TAK‐500, a TAK‐202‐derivative iADC conjugated to an interferon pathway agonist payload TAK‐676, were generated at Takeda Pharmaceuticals International Inc. (Cambridge, MA, USA).

Techniques: Concentration Assay, Clinical Proteomics

Journal: Clinical and Translational Science

Article Title: Population‐Based Modeling to Predict Human PK / PD of TAK ‐500, an Anti‐CCR2 Antibody–Drug Conjugate for First‐in‐Human Study in Cancer Patients

doi: 10.1111/cts.70522

Figure Lengend Snippet: TAK‐500 population PK projections in humans post 1 h IV infusion. The plots (A) represent simulation of PK profile of total antibody and conjugated payload in human population and (B) represent CCR2‐receptor occupancy on the surface of the monocytes by total antibody of TAK‐500 when dosed at 50, 150, and 500 μg/kg, administered intravenously for 1 h. Prediction intervals are calculated from 1000 simulations representing 90% PI. The projections are made for ADC with DAR 4. ADC, antibody drug conjugate; DAR, drug antibody ratio; PI, prediction interval; RO, receptor occupancy.

Article Snippet: Murine antihuman CCR2 mAb (Mu1D9), humanized anti‐hCCR2 monoclonal antibody (TAK‐202), a mouse anti‐TAK‐202 idiotypic antibody, and TAK‐500, a TAK‐202‐derivative iADC conjugated to an interferon pathway agonist payload TAK‐676, were generated at Takeda Pharmaceuticals International Inc. (Cambridge, MA, USA).

Techniques: