CNTO 888) Concentration Time Data

Pharmacokinetics and Pharmacodynamics

The Journal of Clinical Pharmacology Utilizing Pharmacokinetics/Pharmacodynamics 53(10) 1020–1027 ©2013, The American College of Modeling to Simultaneously Examine Clinical Pharmacology DOI: 10.1002/jcph.140 Free CCL2, Total CCL2 and Carlumab (CNTO 888) Concentration Time Data

Gerald J. Fetterly, PhD1, Urvi Aras, PhD1, Patricia D. Meholick, MS1, Chris Takimoto, MD, PhD2, Shobha Seetharam, PhD2, Thomas McIntosh, MS2, Johann S. de Bono, MD, PhD3, Shahneen K. Sandhu, MD3, Anthony Tolcher, MD4, Hugh M. Davis, PhD2, Honghui Zhou, PhD, FCP2, and Thomas A. Puchalski, PharmD2

Abstract The chemokine ligand 2 (CCL2) promotes angiogenesis, tumor proliferation, migration, and metastasis. Carlumab is a human IgG1k monoclonal antibody with high CCL2 binding affinity. Pharmacokinetic/pharmacodynamic data from 21 cancer patients with refractory tumors were analyzed. The PK/PD model characterized the temporal relationships between serum concentrations of carlumab, free CCL2, and the carlumab–CCL2 complex. Dose‐dependent increases in total CCL2 concentrations were observed and were consistent with shifting free CCL2. Free CCL2 declined rapidly after the initial carlumab infusion, returned to baseline within 7 days, and increased to levels greater than baseline following subsequent doses. Mean predicted half‐lives of carlumab and carlumab–CCL2 complex were approximately 2.4 days and approximately 1 hour for free CCL2. The mean dissociation constant (KD), 2.4 nM, was substantially higher than predicted by in vitro experiments, and model‐based simulation revealed this was the major factor hindering the suppression of free CCL2 at clinically viable doses.

Keywords soluble ligand, PK/PD modeling, cytokine

CC‐chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein‐1, is a CC‐chemokine which acts through chemokine receptor 2.1–3 CCL2 promotes tumor inﬂammation, survival, angiogenesis, and metastasis in a variety of cancer types, including breast,4,5 lung,6 esophageal,7,8 and gastric9 carcinomas, as well as 1PK/PD Core Facility, Department of Medicine, Roswell Park Cancer melanoma,10,11 squamous cell carcinoma of the head Institute, Buffalo, New York 2 and neck,12 and hemangiomas.13,14 CCL2 is an important Janssen Research & Development, LLC, Spring House, Pennsylvania 3Drug Development Unit, Royal Marsden NHS Foundation Trust and stimulator in a model of human tumor cell angiogene- The Institute of Cancer Research, Sutton, UK 4,5,15 sis, and it has been proven to be a potent attractor for 4START (South Texas Accelerated Research Therapeutics), San monocytes and macrophages, especially tumor‐associated Antonio, Texas macrophages that have been implicated in the promotion of tumor growth and metastasis.4,5,16 In malignant tumors, Submitted for publication 29 January 2013; accepted 23 June 2013. high levels of CCL2 have been correlated with active Corresponding Author: angiogenesis, stimulated cancer cell proliferation, en- Thomas Puchalski, PharmD, Biologics Clinical Pharmacology, Janssen hanced metalloproteinase production, tumor aggres- Research & Development, LLC, 1400 McKean Road, PO Box 776, siveness, poor prognosis, and early relapse in patients.4,5 Spring House, PA 19477. Email: [email protected] Carlumab (formerly CNTO 888) is a human immuno- Author disclosures: Chris Takimoto, Shobha Seetharam, Thomas globulin G1 kappa monoclonal antibody with activity McIntosh, Hugh M. Davis, Honghui Zhou, and Thomas A. Puchalski against the soluble ligand CCL2 and is currently being are or were employees of Janssen Research & Development, LLC. at the evaluated as a potential therapeutic agent for the treatment time of the study and own(ed) stock in Johnson & Johnson. Gerald J. of solid tumors. Carlumab can neutralize CCL2 activity in Fetterly declares no conflicts of interest. Urvi Aras is an employee of 17 Bristol Myers Squibb. Patricia D. Zagst declares no conflicts of interest. vivo by binding to free CCL2 in the blood. It also Johann S. de Bono declares no conflicts of interest. Anthony Tolcher inhibits macrophage inﬁltration, prevents tumor angio- serves as an uncompensated consultant to Janssen Research & genesis, and decreases tumor vessel density.18 Inhibiting Development, LLC. Shahneen K. Sandhu declares no conflicts of interest. Fetterly et al 1021

CCL2 has the potential to reduce the number of provided informed written consent before any study drug macrophages and monocytes infiltrating tumor tissue, was administered. thereby modulating tumor inflammation and potentially Carlumab was measured in serum using an electro- decreasing tumor cell proliferation. chemiluminescence‐based immunoassay (ECLIA) with a Twenty‐five percent of US Food and Drug Adminis- lower limit of quantification (LLOQ) of 0.078 mg/ml. The tration‐approved antibody products fall into an important carlumab–CCL2 complex was measured in serum using subclass of agents that target soluble ligands.19 In the an ECLIA with a LLOQ of 300 pg/ml. Free serum CCL2 oncology field, little data characterizing the effects of was assayed using an initial Protein A‐based separation antibody on the target ligand are available. Utilizing a method followed by analysis using a commercial CCL2 pharmacokinetics/pharmacodynamics (PK/PD) modeling ELISA assay kit with a LLOQ of 78 pg/ml. approach to examine the interaction between the antibody Samples were collected for carlumab PK analysis prior and the target can provide insight into the turnover of the to and immediately after completion of the IV infusion. target and the binding affinity of the antibody. Additionally, for the first and fourth infusion, samples The overall goal of this modeling exercise was to were collected at 4 and 24 hours post‐infusion, and on devise a carlumab dosing strategy that would optimally Days 8, 15, 18, 22, and 25 post‐infusion. decrease CCL2 concentrations and prolong the length of For determination of serum concentrations of free time that free CCL2 concentrations are suppressed. The CCL2 and the carlumab–CCL2 complex, samples were specific objectives of our analyses were (1) to develop a collected prior to the infusion, 24 hours post‐infusion, and mechanistic PK/PD model to simultaneously characterize on Days 8, 15, and 22 post‐infusion following the first the serum concentration‐time profiles of carlumab, free administration of carlumab. For the second and third CCL2, and the carlumab–CCL2 complex and (2) to administrations, samples were only collected prior to the simulate free CCL2 concentrations following administra- infusion. For the fourth administration, samples were tion of various carlumab dose regimens in order to gain a collected prior to the infusion and 24 hours post‐infusion. better understanding of the effects of carlumab on free Additional samples were collected during follow‐up visits CCL2 and the carlumab–CCL2 complex. at Weeks 8, 12, and 18.

Modeling Software Methods Population PK/PD modeling and simulation were per- Phase 1 Study of Carlumab in Malignant Solid Tumors formed using the maximum likelihood estimation method Details of the study design and results will be reported (MLEM) in ADAPT 5. Statistical analyses and graphing elsewhere.20 In brief, this first‐in‐human study of were performed using SAS Version 9.1, and Prism 5 was carlumab was an open‐label, multiple administration, used for plotting model‐based simulations. ascending‐dose study designed to determine the safety and PK of carlumab. Patients received a 90‐minute IV PK/PD Model infusion of carlumab, followed by a 4‐week monitoring A PK/PD model that incorporated target binding was used period to assess the single‐dose PK profile of carlumab. to simultaneously characterize the concentration‐time Three subsequent doses of carlumab were administered profiles of carlumab, the soluble ligand target, CCL2, every 2 weeks following the end of the monitoring period. and the carlumab–CCL2 complex in serum (Figure 1). In the dose‐escalation phase of the study, a total of 5 Several models were tested that incorporated the cohorts were evaluated at doses of 0.3, 1, 3, 10, or 15 mg/ relationship between the drug and the drug–receptor kg. Three patients were included in each cohort dosed at complex, but ultimately a quasi‐equilibrium model of 3 mg/kg, and 6 patients were included in each of the 10 target‐mediated drug disposition (TMDD) was used to and 15 mg/kg dose cohorts. The dose‐expansion phase analyze the available data.21 consisted of patients receiving either 10 or 15 mg/kg of Based on the pharmacological mechanism of action of carlumab at 2‐week intervals. Data from only the dose‐ drug–receptor complexes described by TMDD, IV escalation phase were used to develop the PK/PD model administered carlumab may distribute to and from tissue due to the robust amount of carlumab, free CCL2, and binding sites (k3 and k4) or may be eliminated from the carlumab–CCL2 complex serum concentration‐time central compartment by degradation (kdeg). Carlumab, information available from this phase of the study. Key which has a half‐life of approximately 2.4 days, binds to patient eligibility criteria included the presence of type‐ free CCL2 ligands, which have half‐lives of approximately specific solid tumors that had progressed after all 1 hour when present in the blood. Free CCL2 is assumed to available standard therapy, and measurable or evaluable be produced at a zero‐order rate of Ksyn and has a baseline metastatic disease. The study was conducted in accor- value of Rss. Free CCL2 also is assumed to distribute dance with the principles of the Declaration of Helsinki between tumor tissue and blood, and is eliminated from the and was approved by institutional review boards. Patients blood at a rate of Kdeg,free ligand. The formed complex is 1022 The Journal of Clinical Pharmacology / Vol 53 No 10 (2013)

Ksyn

carlumab CCL2 Tumor / Tissue

K K K Blood 3 4 2

KD carlumab CCL2 complex Drug Admin 1 mole of carlumab binds 1 mole of CCL2 Kdeg, Kdeg, Kdeg, carlumab-CCL2 carlumab free CCL2 complex

Figure 1. Simultaneous PK/PD model of carlumab, free CCL2, and carlumab–CCL2 complex. eliminated at a rate of Kdeg complex, such that the rate of The serum concentration‐time course of free carlumab degradation of the complex is much slower than that of free (CCarlumabfree ) is described by the following equation: CCL2, but is similar to that of unbound carlumab. Ktr is the transfer rate between the complex and the free drug. 1 Ccarlumab ¼ Ccarlumab R KD As the binding and dissociation of the carlumab–CCL2 free 2 tot CCL2tot qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi complex is assumed to be more rapid than the other system þ ðÞ 2 þ processes, and equilibrium between binding and dissocia- Ccarlumabtot RCCL2tot KD 4KDCcarlumabtot tion is achieved almost instantly, limited information about ð Þ these processes can be obtained.21 Therefore, by assuming 5 that the concentrations of carlumab (Ccarlumab), free ligand The initial conditions for all equations were set to 0, – (CCL2 or RCCL2), and the carlumab CCL2 complex whereas the baseline ligand concentrations were estimated (RCcomplex) are at quasi‐equilibrium, the equilibrium as Rss. Also, RCCL2tot represents the total amount of CCL2, dissociation constant, KD, can be used to describe the both free and bound to the drug–ligand complex. – binding and dissociation of the drug ligand complex. The The equations for carlumab, CCL2, and carlumab– rates of change of all 3 variables (carlumab, free CCL2 and CCL2 complex were assessed using a population analysis – fi carlumab CCL2 complex) were de ned using the follow- using a mixed effects modeling approachwiththe equations ing model: being solved simultaneously to estimate the model parameters using MLEM implemented in ADAPT 522 dC carlumabtot ¼ð þ Þ with a proportional error variance model for residual error; KdegmAb K3 Kdegcomplex dt Var(Y) ¼ (Slope • Y)2. Model selection, comparison, C var carlumabfree and the choice of final structural models, were guided using K A lnðtÞ þ 4 carlumabTissue þ ð1Þ the likelihood ratio test, the precision of the parameter V K C V c degcomplex carlumabtot c estimates, and diagnostic plots (observed concentrations vs. individual and population predicted concentrations, dA weighted residuals vs. predicted time and concentrations). carlumabtissue ¼ K C V K dt 3 carlumabfree c 3 The inter‐patient variability in PK/PD parameters was ð Þ Acarlumabtissue 2 assumed to be log normally distributed. A change in 2 • log likelihood of at least 3.84 (a < 0.05, 1 df) was used to dR R fi fi CCL2 ¼ þð CCL2ss Þ ð Þ de ne statistical signi cance for addition or deletion of a Ksyn K2 RCCL2 3 dt Kdegfree K2 single parameter during the model building process. Model discrimination was accomplished according to the “rule of dRC R ” ’ 23 complex ¼ þ CCL2ss parsimony based on Akaike s information criterion. KTR RCCL2free dt Kdeg K2 free ð4Þ Model‐Based Simulations of CCL2 Response for K K C C degcomplex degfree P Multiple Dosing Scenarios Model‐based deterministic simulations were performed K R degfree CCL2tot using the SIM (population with output error) option in Fetterly et al 1023

ADAPT 5 to examine the dose‐response relationships provided a relatively unbiased fit to the data for both between carlumab, free CCL2, and the carlumab–CCL2 carlumab and carlumab–CCL2 complex. Free CCL2 was complex. Simulations were performed without interindi- predicted reasonably well, but the recovery to baseline vidualvariabilityduetothelimiteddataandheterogeneityin values seemed to be overpredicted, providing a conserva- tumor subtype at baseline. Various dosing regimens of tive estimation of the availability of free CCL2 following carlumab were simulated to target a 90% reduction in free carlumab administration. Serum concentration‐time pro- CCL2 concentration. As a result, multiple schedules were files of intravenous carlumab revealed a rapid rise in selected that would cause a rapid drop in free CCL2 and carlumab serum concentration during the infusion maintain concentrations below the range of 80–125 pg/ml. followed by a poly‐exponential decay post‐infusion Simulations were also performed to compare the effects of (Figure 2). Carlumab–CCL2 complex concentrations numerous dosing schedules using KD values estimated by increased by 1,000‐fold from baseline to Day 8 in patients the PK/PD model to KD values obtained in vitro using a receiving 10 and 15 mg/kg doses of carlumab. For the surface plasmon resonance platform (Biacore Life other doses, a large, rapid, dose‐dependent increase was Sciences). observed in carlumab–CCL2 complex concentrations The dose–response relationships of carlumab were following study drug administration. Increases in carlu- examined at the following dosing regimens and KD values: mab–CCL2 complex concentrations are consistent with (a) 2.5 and 5 mg/kg both weekly and 3 times weekly at a binding free CCL2, which is rapidly cleared in the absence KD of 2,400 pM (estimated value from PK/PD model), (b) of carlumab but is cleared much more slowly when bound 25 mg/kg weekly at a KD of 150 pM (10‐fold higher than to the drug. After approximately 4–5 days post‐dosing, the estimated in vitro value), and (c) 12.5 and 25 mg/kg carlumab–CCL2 complex concentrations declined in both weekly and 15 mg/kg twice weekly at a KD of 15 pM parallel with the carlumab serum concentrations. (estimated in vitro value). For all dose levels following the first administration, a rapid decrease of free CCL2 concentrations was observed, Study Highlights followed by a recovery of free concentrations to Examining monoclonal antibodies and target engagement endogenous baseline values. For the 10 and 15 mg/kg with direct assessments of free ligand and drug‐ligand dose levels, free CCL2 concentrations were up to 3‐fold complex have been rare to date within oncology, although above baseline at Day 7 following the first and subsequent previously utilized within immunology studies. A mecha- administrations. Additionally, for all dose levels, at nistic PK/PD model was developed for carlumab, a human 24 hours after the fourth administration, there was a rapid monoclonal antibody using principles of TMDD. Based on reduction of free CCL2 concentrations. This was similar in the modeling results, simulations showed that administra- magnitude to the rapid transient suppression of CCL2 tion of the highest commercially viable dose of 25 mg/kg concentrations observed at 24 hours after the first weekly, carlumab was unable to continually suppress free administration of carlumab, although free serum CCL2 CCL2.CarlumabwasabletoneutralizefreeCCL2levelsfor concentrations were not substantially reduced below the only a short period of time at this dose. For other mono- baseline. clonal antibody developed drugs, these results underscore Based on the observed data and the known mechanism the importance of understanding both the kinetics of the of action of carlumab, a PK/PD model with tissue target and the in vivo binding affinity of the antibody. distribution of carlumab, and transfer of the target from the tissue space to blood, was used to simultaneously Results describe the time course of carlumab, carlumab–CCL2 complex and free CCL2 serum concentrations. The Demographics Twenty‐one patients were enrolled in the study, of which parameter estimates of the base structural PK/PD model are displayed in Table 1. Predicted and observed 10 were female (48%). Patients had various tumor types – and 91% had an Eastern Cooperative Oncology Group concentration time plots for the PK/PD model after a (ECOG) status of 0–1. Median (range) age was 63 (range dose of 15 mg/kg revealed that the model provided a relatively unbiased fit to the data (Figure 2). Free CCL2 23, 81), years and 95% were Caucasian. Carlumab, free – concentrations were overpredicted in comparison to CCL2, and carlumab CCL2 complex levels were collect- – ed from 325 records for PK/PD modeling.20 A total of 2 carlumab and the carlumab CCL2 complex in many patients. The percent coefficient of variation (%CV) for patients (at the 3 and 10 mg/kg dose levels; respectively) had an immune response to CNTO 888. the population mean parameter estimates ranged from 24 to 127%. The estimated KD for the binding of carlumab Carlumab, CCL2, and carlumab–CCL2 Complex Serum to CCL2 was estimated to be 2.4 nM (71.5%CV). This Levels value is 160‐fold higher than the in vitro KD of 15 pM Predicted and observed concentration–time and goodness‐ measured by the Biacore method. The estimated baseline of‐fit plots for the PK/PD model revealed that the model concentration of free CCL2 was 0.0702 nM, which 1024 The Journal of Clinical Pharmacology / Vol 53 No 10 (2013)

Figure 2. (A) Goodness‐of‐fit plots of carlumab, free CCL2, and carlumab–CCL2 complex. (B) Comparison of predicted and observed PK/PD profiles of carlumab, free CCL2, and carlumab–CCL2 complex for the 15 mg/kg dose level. equates to 913 pg/ml. This concentration is comparable to 0.09 L/kg, which is about 6.3 L for a patient with a body published values of basal CCL2 that range from 200 to weight of 70 kg. 700 pg/ml. Interestingly, the elimination rate constants for both carlumab and the carlumab–CCL2 complex CCL2 Response for Multiple Dosing Scenarios resulted in a half‐life of approximately 2.4 days. The Model‐based simulations were used to predict clinically plasma volume of distribution, (Vc), was estimated to be relevant free CCL2 suppression after carlumab Fetterly et al 1025

Table 1. Estimated Population PK/PD Model Parameters for Carlumab value 10 times higher than the in vitro value, and the PK/ PD model‐derived K value. Parameter (units) Mean %CVa D When the in vitro value of 15 pM from the Biacore Kdeg, carlumab (1/hour) 0.0122 34.7 method was used in simulations, concentrations of free K3 (1/hour) 0.288 58 CCL2 were reduced 160‐fold from baseline and were K4 (1/hour) 0.738 33.7 maintained below a target range of 80–125 pg/ml after K (nM 1/hour) 0.0228 58 syn administration of carlumab at 12.5 mg/kg once weekly, K2 (1/hour) 0.325 45.9 K (nM) 2.4 71.5 15 mg/kg twice weekly or 25 mg/kg once weekly D ‐ Kdeg, carlumab–complex (1/hour) 0.0106 127 (Figure 3A); however, using the model estimated KD of

Kdeg, free CCL2 ligand (1/hour) 0.838 47 2.4 nM following a dose of 15 mg/kg once weekly, Vc (L/kg) 0.0896 24 concentrations of free CCL2 were reduced approximately Rss (nM) 0.0702 58 two‐fold from baseline and values returned to near a baseline within 7 days after carlumab administration Coefficient of variation of the estimate; reflects interpatient variability. (Figure 2). Lower doses of carlumab administered more frequently were also examined. A similar effect on free CCL2 was observed following administration of administration. Since there were discrepancies between carlumab at 2.5 and 5 mg/kg twice and three times model‐estimated values and in vitro derived KD values, we weekly (Figure 3B,C). Free CCL2 values were not used simulations to evaluate the extent and duration of free maintained below a target range of 80–125 pg/ml, CCL2 suppression from baseline values using various KD even after administration of a higher dose of carlumab values that included the in vitro Biacore‐derived KD,a at 25 mg/kg once weekly (Figure 3D).

Figure 3. (A) Free CCL2 concentrations after administration of carlumab 15 mg/kg twice weekly, 25 mg/kg once weekly, and 12.5 mg/kg once weekly

(simulated KD 15 pM). (B) Free CCL2 concentrations after administration of carlumab 2.5 mg/kg twice and three times weekly (simulated KD 2,400 pM). (C) Free CCL2 concentrations after administration of carlumab 5 mg/kg twice or three times weekly (simulated KD 2,400 pM). (D) Simulation of free CCL2 concentrations after administration of carlumab 25 mg/kg once weekly at various KD values. Free CCL2 levels should be suppressed below the target range of 80–125 pg/ml, baseline CCL2 levels can range from 200 to 700 pg/ml. 1026 The Journal of Clinical Pharmacology / Vol 53 No 10 (2013)

To understand the major determinant of the lack of circulation will be similar to the effect in the tumor CCL2 suppression to below baseline levels throughout compartment. dosing, we conducted simulations using different KD To better define the physiological relevance of the PK/ values following repeat administration of carlumab at a PD model and the parameter estimates, we conducted a dose of 25 mg/kg every week (Figure 3D). This dose thorough cynomolgus monkey PK/PD study.24 The results would most likely be the highest commercially viable from this study support the model structure, since there did dose, and previous preclinical data suggest that, using this not appear to be a dose‐related increase in CCL2 dose and schedule, all free CCL2 in the serum would be production rate. In addition, the model‐derived binding 24 bound and complexed by carlumab. When the KD was affinity, CCL2 elimination rate and CCL2 production rate fixed to the in vitro value of 15 pM, continuous are in good agreement with the values obtained from the suppression to at least 95% of baseline was observed preclinical study. These findings support that the throughout treatment. If the in vivo KD was 10‐fold higher modeling, and the simulation results are scientifically than the in vitro value, then continuous suppression of robust. CCL2 to below baseline occurred; however, using a value An in vitro binding constant for the drug–ligand in the range of the model prediction of 2 nM, suppression interaction between carlumab and CCL2 was estimated to of CCL2 to below baseline was only observed in the first be 15 pM. In contrast, the model‐estimated binding 2 days of the 7‐day treatment schedule. These data suggest constant was 2.4 nM, which was 160‐fold higher than that the major determinant of the inability of carlumab to the in vitro estimated value. One possible explanation for suppress CCL2 in humans is due to the unexpected high in the discrepancy between model‐predicted and observed in vivo KD value observed in patients. vitro binding affinity may be due to the lack of human proteins in the determination of the in vitro binding affinity. In addition, there is slight evidence of the Discussion formation of anti‐carlumab antibodies in 2 patients that In this study, a PK/PD model using the principles of could be a plausible explanation for the higher KD value. TMDD was developed. The mechanistic PK/PD model The patients who illustrated the presence of anti‐carlumab described the carlumab, free CCL2, and carlumab–CCL2 antibodies were at the 3‐ and 10‐mg/kg dose levels had an complex concentration‐time data simultaneously in immune response to drug with titers of 1:50 and 1:25, serum. The results from this model support a PD respectively, and had no apparent effect on pharmacoki- mechanism whereby carlumab binds to CCL2, resulting netic behavior of carlumab. Also, this discrepancy in KD in a biologically inactive drug–target complex. The PK/ values was further supported by a study in cynomolgus PD model was evaluated by comparing Cmax and the area monkeys. under the curve (AUC) for carlumab, free CCL2 and Using the model‐derived binding constant, we simu- carlumab–CCL2 complex, utilizing noncompartmental lated concentration–time profiles of the 3 analytes PK methods (results not shown). The findings revealed following numerous carlumab dosing scenarios ranging good concordance between the observed data and model from 2.5 to 25 mg/kg administered once, twice, or three predicted parameters (results not shown). times weekly. Baseline serum concentrations of CCL2 In oncology, examining target engagement of mono- typically range from 200 to 700 pg/ml, and a prolonged clonal antibodies using direct assessments of free ligand suppression of CCL2 values less than 80–125 pg/ml after and drug‐ligand complex data have been rare to date. carlumab administration was considered optimum based However, within immunology, these assessments were on receptor theory. Therefore, dosing regimens were integral for the selection of omalizumab dose and selected to ideally produce a rapid drop in free CCL2 schedule.25 Specifically, PK/PD modeling showed a concentrations and to maintain a target concentration strong correlation between continuous suppression of below the range of 80–125 pg/ml. serum IgE, the target of omalizumab, and clinical activity. Simulations based on an in vitro estimated KD showed These data support the hypothesis that continuous that prolonged suppression of free CCL2 concentrations to suppression of a soluble ligand in the systemic circulation below baseline values following carlumab administration is needed to achieve therapeutic benefit. should be achievable at the dosing regimens used in this We planned on modeling carlumab binding CCL2 clinical trial; however, when the higher model‐derived KD within the tumor compartment; however, the small value was used, these simulations showed that free CCL2 number of biopsies and technical challenges to develop concentrations were only transiently suppressed and a sensitive method did not allow for a robust examination quickly returned to baseline values (200–700 pg/ml) or of free CCL2 and carlumab–CCL2 complex within this increased beyond the needed target suppression range compartment.20 Based on the modeling, the distribution of (80–125 pg/ml) within 7 days after each dose. These CCL2 from the tumor and tissue compartments was rapid. findings indicated that even after dosing at the highest This suggests that the effect within the systemic clinically viable dose of 25 mg/kg weekly, carlumab was Fetterly et al 1027 unable to sustain a prolonged suppression of free CCL2 10. Graves DT, Barnhill R, Galanopoulos T, Antoniades HN. Expres- concentration and was only able to neutralize CCL2 levels sion of monocyte chemotactic protein‐1 in human melanoma in vivo. – for a limited period of time. In addition, there is no Am J Pathol. 1992;140:9 14. 11. Nesbit M, Schaider H, Miller TH, Herlyn M. Low‐level monocyte evidence that CCL2 levels in circulation are different from chemoattractant protein‐1 stimulation of monocytes leads to tumor those in tumor tissues. These clinical findings are formation in nontumorigenic melanoma cells. J Immunol. 2001; consistent with the binding of the high turnover target, 166:6483–6490. CCL2, forming carlumab–CCL2 immune complexes. 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Relationship protein‐1 expression correlates with macrophage infiltration and between omalizumab pharmacokinetics, IgE pharmacodynamics tumor vascularity in human gastric carcinomas. Int J Oncol. and symptoms in patients with severe persistent allergic (IgE‐ 2003;22:773–778. mediated) asthma. Br J Clin Pharmacol. 2009;68:61–76. 本文献由“学霸图书馆-文献云下载”收集自网络，仅供学习交流使用。

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