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Keywords:

  • ASKP1240;
  • anti-CD40;
  • pharmacodynamics;
  • pharmacokinetics;
  • randomized

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

This first-in-human, phase I study evaluated the safety, tolerability, pharmacokinetic and pharmacodynamic profile of ASKP1240 in healthy subjects. Twelve sequential groups (each 6 active and 3 placebo) were randomly assigned to placebo or single ascending doses of intravenous ASKP1240 (0.00003–10 mg/kg). ASKP1240 exhibited nonlinear pharmacokinetics, with mean maximal serum concentrations and area under the serum concentration–time curves ranging from 0.7 to 251.6 μg/mL and 6.5 to 55409.6 h·μg/mL following doses 0.1 mg/kg–10 mg/kg, respectively. CD40 receptor occupancy by ASKP1240, which was dose-dependent, reached a maximum at doses above 0.01 mg/kg. ASKP1240 was well tolerated, with no evidence of cytokine release syndrome or thromboembolic events. Treatment emergent antibodies to ASKP1240 were detected in 5/70 (7.1%) ASKP1240 recipients. In conclusion, antagonism of the CD40/CD154 interaction with ASKP1240 was safe and well tolerated at the doses tested.


Abbreviations
AEs

adverse events

AUCinf

area under the concentration-time curve from time zero extrapolated to the infinite time

Cmax

maximal antibody serum concentration

INR

international normalized ratio

LLOQ

lower limit of quantification

MABEL

minimal anticipated biological effect level

MedDRA

Medical Dictionary for Regulatory Activities

MFI

mean fluorescent intensity

PD

pharmacodynamic

PDAS

pharmacodynamic analysis set

PK

pharmacokinetic

PKAS

pharmacokinetic analysis set

SAF

safety analysis set

SD

standard deviation

t1/2

terminal half-life

tmax

time to Cmax

ULN

upper limit of normal

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

More effective immunosuppressive agents are required to prevent allograft rejection and minimize the adverse effects associated with current treatments. A promising area of research in the optimization of immunosuppressant therapy involves targeting T cell costimulatory molecules [1, 2].

ASKP1240 is a fully human anti-CD40 monoclonal antibody (IgG4) antagonist that inhibits humoral and cellular immune responses by blocking the CD40/CD154 interaction between T cells, B cells and antigen presenting cells [3]. In vivo, the delayed-type hypersensitivity reaction and antibody production against tetanus toxoid were suppressed in monkeys receiving ASKP1240 [4]. Kidney transplant studies in cynomolgus monkeys indicated that ASKP1240 prolonged allograft survival without evidence of serious adverse events (AEs) [3, 5].

The purpose of this study was to evaluate the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profile of ASKP1240 after single escalating doses in healthy subjects.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

Study design

This single-center, randomized, double-blind, placebo-controlled, single dose escalating study was approved by the Chesapeake Research Review Inc. Institutional Review Board (protocol number, 7163-CL-0101; ClinicalTrials.gov identifier: NCT01279538). The study was conducted at PAREXEL International Early Phase Clinical Unit-Baltimore, Harbor Hospital, Baltimore, MD, USA in compliance with the Good Clinical Practice guidelines and the principles of the Declaration of Helsinki.

Participants

Eligible male and female subjects gave written informed consent, and were in good health. Key inclusion criteria were 18–45 years of age, ≥50 kg in weight and BMI of 18–32 kg/m2. Exclusion criteria were any significant past medical history or abnormal laboratory tests.

Interventions

The test drug was ASKP1240 (supplied by Kyowa Hakko Kirin Co., Ltd. Tokyo, Japan), while the comparator drug (matching placebo) was 0.9% sodium chloride for injection. ASKP1240 was supplied as 4-mL solution containing ASKP1240 40 mg (10 mg/mL) and stored at 2–8°C (36–46°F) protected from light. ASKP1240 was diluted for intravenous administration using either ASKP1240 vehicle (for 0.00003–0.3 mg/kg dose levels) or 0.9% sodium chloride solution (for 1, 3 and 10 mg/kg dose levels).

Treatment regimens

Sequential groups of fasted subjects received a single dose of intravenously administered ASKP1240 at 12 increasing dose levels (0.00003, 0.0001, 0.0003, 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3 and 10 mg/kg). The initial dose (0.00003 mg/kg) was based on one-tenth of the minimal anticipated biological effect level (MABEL) in vitro. ASKP1240 (or placebo) was administered as a short infusion (5 min) via syringe pump for the 0.00003 mg/kg dose level and administered over 30 min via syringe pump or programmable infusion pump for the higher dose levels.

Exposure of subjects to each dose level occurred over 3 days. Sentinel dosing was used with approximately 24 h between dosing cohorts. After all subjects in a dose group had completed study procedures to day 8 (1 week after dosing), a decision on dose escalation and enrollment of the next dose group was made based upon the incidence and severity of reported AEs and safety laboratory test results collected over 1 week after infusion. Escalation to the next dose level occurred in the absence of dose-limiting toxicity or other significant safety findings.

Randomization and blinding

Within each dose group, eligible subjects were randomized to either active drug or placebo according to a randomization schedule generated by the Sponsor. As the appearance of placebo was the same as diluted ASKP1240 for infusion, the study blind was maintained during the administration procedure.

Pharmacokinetics

Serial blood samples for PK assessments were collected at the following timepoints relative to infusion start time: predose and postdose at hours 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 (day 2), 36 (day 2), 48 (day 3), 72 (day 4), 96 (day 5), 120 (day 6), 144 (day 7) and 168 (day 8) and days 15, 22, 29, 43, 60, 75 (10 mg/kg dose group only) and 90 (10 mg/kg dose group only).

Concentrations of ASKP1240 in serum were determined using a validated method involving sandwich immunoassay with electrochemiluminescence detection (MSD Sector Imager 6000, MSD, Gaithersburg, MD, USA; Ref. [6]. The lower limit of quantification (LLOQ) for the assay was 81.92 ng/mL. This method was linear over the range of 81.92–50 000 ng/mL. The overall precision and accuracy of the quality controls and standards were ≤20% and within ±20%, respectively. A standard curve was constructed by use of a four-parameter logistic model enabling sample concentrations to be estimated by interpolation from the fitted curve.

Individual serum concentration–time data were used to calculate ASKP1240 PK parameters using noncompartmental analysis with WinNonlin PK software (version 5.3, Pharsight, Mountain View, CA, USA). The maximum concentration in serum (Cmax) and the time to Cmax (tmax) were the observed values. Values below the LLOQ were set to zero for calculation of descriptive statistics and in the estimation of individual PK parameters. The area under the concentration–time curve from 0 to infinity (AUCinf) was calculated using the linear-log trapezoidal method. The terminal-phase elimination rate constant (kel) was calculated as the negative slope of the log-linear terminal portion of the serum drug concentration–time curve using linear regression. The half-life (t1/2) of the terminal elimination phase was estimated by use of the following equation: In(2)/kel.

Pharmacodynamics

Blood samples for CD40 receptor occupancy were collected at the following timepoints relative to infusion initiation: predose and postdose at hours 0.25 (for 5-min infusion), 0.5 (for 30-min infusion), 24 (day 2), 48 (day 3), 96 (day 5) and 168 (day 8) and days 15, 22, 29, 43, 60 (10 mg/kg dose group only) and 75 (10 mg/kg dose group only)., Samples were exposed to an excess of biotinylated ASKP1240. As a result, previously unbound CD40 sites were occupied by a bound biotinylated ASKP1240 monoclonal antibody. A fluorochrome-tagged streptavidin solution was used to fluorescently label all of the bound biotinylated ASKP1240. Flow cytometry was used to determine ASKP1240 binding to CD40 receptors on CD20 positive B cells (MEDTOX Laboratories, Inc., St. Paul, MN, USA). The geometric mean fluorescent intensity (MFI) of the bound biotinylated ASKP1240 was determined and reported. The MFI was directly proportional to the number of unbound CD40 sites on B cells at various ASKP1240 concentrations. CD40 receptor occupancy at each sampling time was calculated as follows:

  • display math

Total lymphocyte count and peripheral lymphocyte subsets (CD3, CD4, CD8, CD16 and CD19) were determined from separate samples collected at common timepoints: screening, day 1 (total lymphocyte count only), predose and postdose at hours 2, 24 (day 2), 48 (day 3), 96 (day 5) and 168 (day 8) and days 15, 22, 29, 43 and 60.

Immunoassessment

Blood samples for anti-ASKP1240 antibody detection were collected at screening and on day 1 (predose), days 8, 15, 29 and 43, 60 (1 and 3 mg/kg groups only), 75 and 90 (10 mg/kg dose group only) or in the event of early discontinuation. Titering of anti-ASKP1240 antibodies in serum was performed using a validated electrochemiluminescence, bridging immunogenicity assay [7].

Coagulation assessments

Tests of the coagulation pathway included the following: D-dimer (fragment D-dimer, fibrin degradation fragment), prothrombin time, activated partial thromboplastin time, fibrinogen level, prothrombin fragments 1 and 2 and INR. Platelet function was assessed using the PFA-100 platelet function analyzer. Platelet activity was assessed by aggregometry of platelets and leukocytes. Endothelial cell activation was assessed by quantification of soluble E selectin (CD62E) in plasma, and monocyte activation was assessed via MAC-1 (CD11b) expression on monocytes (CD14+ cells).

Safety assessments

The safety of ASKP1240 was assessed by the incidence of AEs, anti-ASKP1240 antibody formation, cytokine (IL-2, IL-6, IL-12, tumor necrosis factor-alpha and interferon gamma) concentrations, clinical laboratory evaluations, 12-lead electrocardiograms, vital signs, physical examination and pulse oximetry. The relationships between study medications and AEs were evaluated by the investigators at the site.

Analysis populations

The following populations were defined for analyses: (1) safety analysis set (SAF)–-the subset of all enrolled subjects who received ≥1 dose of study drug; (2) PK analysis set (PKAS)—the subset of subjects from the SAF whose PK data were adequate, as defined by the pharmacokineticist, for the calculation of the primary PK parameters; and (3) PD analysis set (PDAS)—the subset of subjects from the SAF whose PD data were adequate for the assessment of PD parameters. All analyses were based on treatment assignment.

Statistical methods

This study was conducted to assess the safety, tolerability, PK and PD profile of ASKP1240 after a single intravenous dose at escalating dose levels in healthy subjects. While no statistical methods were used to determine the sample size, the planned sample size of 108 subjects (nine subjects per dose level, six active and three placebo) is consistent with other PK studies of similar design. Percentages by categories were based on the number of subjects with no missing data. No imputation of missing data was performed.

Dose proportionality was evaluated using the power model on the primary PK parameters AUCinf and Cmax:

  • display math

A 95% confidence interval of the slope estimate “b” (after natural log transforming both sides) was used to evaluate the dose proportionality of the dose groups. Dose proportionality was concluded if the 95% confidence interval for “b” included 1.

Descriptive statistics were used to characterize all PD parameters.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

Participant flow

Of the 109 subjects randomized, 108 subjects received treatment (Figure 1). The 108 subjects who received treatment comprised both the SAF and the PDAS. The PKAS included all 72 subjects who received ASKP1240. The first subject was enrolled on January 26, 2009. The last subject evaluation was December 19, 2009. No subject discontinued due to an AE or was discontinued from the study or removed from an analysis set due to a protocol violation or deviation. Three subjects were lost to follow-up and one subject withdrew consent.

image

Figure 1. Consort diagram of study subjects. *Safety-analysis set (all randomized subjects who received at least 1 dose of study drug). †For every subject, only the primary reason for discontinuation was collected.

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Baseline data

Subject demographics are shown in Table 1. African Americans accounted for at least half of the subjects in all but one treatment group (ASKP1240 0.0001 mg/kg) with most of the remaining subjects being white. The age, weight and BMI of all subjects fell within the inclusion criteria defined in the protocol.

Table 1. Subject demographics at baseline in the SAF
VariablePlacebo (N = 36)Total ASKP1240 (N = 72)
Sex, N (%)
 Male34 (94.4)66 (91.7)
 Female2 (5.6)6 (8.3)
Race, N (%)
 White9 (25.0)27 (37.5)
 Black/African American27 (75.0)41 (56.9)
 Other04 (5.6)
Ethnicity, N (%)
 Not Hispanic/Latino35 (97.2)68 (94.4)
 Hispanic or Latino1 (2.8)4 (5.6)
Age (years), mean ± SD (range)33.1 ± 8.0 (18–45)33.0 ± 7.1 (20–45)
BMI (kg/m2), mean ± SD (range)25.8 ± 3.4 (18.4–31.1)26.9 ± 3.0 (19.4–32.0)

Pharmacokinetics

All serum ASKP1240 concentrations in subjects who received the lowest six doses (0.00003–0.01 mg/kg) of ASKP1240 were below the LLOQ, as were most concentrations in subjects who received the 0.03 mg/kg dose. Figure 2 illustrates the ASKP1240 concentration-time data for the remaining dose groups.

image

Figure 2. Mean serum ASKP1240 concentrations (semi-log scale) from pre-dose to end of study in the PKAS. Treatment groups shown are 0.1 mg/kg (○), 0.3 mg/kg (▪), 1.0 mg/kg (▴), 3.0 mg/kg (•) and 10.0 mg/kg (⋄). N = 5–6 subjects per treatment group.

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Mean ASKP1240 Cmax and AUCinf ranged from 0.7 to 251.6 μg/mL and 6.5 to 55409.6 h.μg/mL following doses 0.1–10 mg/kg, respectively (Table 2). ASKP1240 displayed nonlinear PKs, as evidenced by disproportionate increases in systemic exposure with dose. The slope and its 95% CI for AUCinf and Cmax were 1.99 (1.79, 2.18) and 1.28 (1.18, 1.39), respectively, at the range of 0.1–10 mg/kg.

Table 2. Mean (± SD) PK parameters of single-dose ASKP1240 (0.1–10 mg/kg) in the PKAS
 ASKP1240 treatment groups
Parameter0.1 mg/kg0.3 mg/kg1 mg/kg3 mg/kg10 mg/kg
Cmax (μg/mL)
N65666
Mean ± SD0.7 ± 0.45.4 ± 1.126.0 ± 4.083.7 ± 10.0251.6 ± 36.1
Median (range)0.7 (0.3–1.2)5.5 (4.3–7.1)26.2 (19.3–31.4)82.4 (7.4–100.4)247.2 (209.0–291.3)
tmax (h)
N65666
Mean ± SD0.7 ± 0.31.5 ± 0.51.3 ± 0.61.6 ± 0.62.0 ± 2.0
Median (range)0.5 (0.5–1.0)1.5 (1.0–2.0)1.3 (0.5–2.0)1.8 (0.5–2.0)1.3 (1.0–6.0)
AUCinf (h.μg/mL)
N45666
Mean ± SD6.5 ± 5.2141.1 ± 44.31860.3 ± 403.612315.9 ± 2061.755409.6 ± 12134.0
Median (range)5.9 (0.6 – 13.4)133.5 (98.5 – 208.9)1798.5 (1292.9 – 2348.6)12142.3 (9734.0 – 15610.7)51675.5 (44605.2 – 78726.3)
t1/2 (h)
N45666
Mean ± SD3.9 ± 2.913.0 ± 3.6151.9 ± 201.4127.0 ± 19.8264.7 ± 109.0
Median (range)3.5 (0.8–7.8)14.1 (9.0–16.8)59.2 (47.1–557.1)128.7 (94.2–154.2)242.4 (179.2–478.1)

Median tmax ranged from 0.5 to 1.8 h and appeared unrelated to dose whereas mean t1/2 of ASKP1240 increased with dose. Clearance of ASKP1240 decreased as the dose increased while the volume of distribution (Vd) calculated based on the terminal elimination phase remained in a similar range across different dose levels.

Pharmacodynamics

ASKP1240 showed dose-dependent B cell CD40 receptor occupancy. There was no significant binding of ASKP1240 to the CD40 receptor at dose levels below 0.01 mg/kg. At doses of 0.01 mg/kg and 0.03 mg/kg, mean maximal CD40 receptor occupancy was approximately 70% and 80%, respectively. However, the duration of receptor occupancy was relatively short and declined within 24 h. As doses increased, the extent of mean maximal CD40 receptor occupancy essentially remained the same; however, the duration of receptor occupancy was gradually prolonged in a dose-dependent manner. The duration of mean maximal receptor occupancy was 48 h, 7 days, 29 days and 60 days for doses of 0.3, 1, 3 and 10 mg/kg, respectively (Figure 3). Mean maximal CD40 receptor occupancy did not exceed 87% since the assay had a background indicative of approximately 10% receptor occupancy.

image

Figure 3. Mean CD40 receptor occupancy for placebo and across ASKP1240 treatment groups (0.3, 1.0, 3.0 and 10.0 mg/kg) from predose to end of study in the PDAS. Treatment groups shown are 0.1 mg/kg (○), 0.3 mg/kg (▪), 1.0 mg/kg (▴), 3.0 mg/kg (•), 10.0 mg/kg (⋄) and placebo (–▪–). N = 5–6 subjects per treatment group.

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Total lymphocyte counts and peripheral lymphocyte counts (performed for subsets CD3, CD4, CD8, CD16 and CD19) showed no consistent change from baseline at any dose level.

Safety

The overall incidence of any AEs was higher in the ASKP1240 treatment groups than in the pooled placebo groups (Table 3). AEs judged by the investigator to be drug-related were experienced by 18 of 72 subjects (25.0%) who received any dose of ASKP1240 and 8 of 36 placebo subjects (22.2%). The most common treatment-emergent AEs that occurred in more than two subjects receiving ASKP1240 are shown in Table 4. Most AEs were mild in intensity, although one severe AE (allergy to arthropod sting) occurred in a subject who had received ASKP1240 10 mg/kg. There were no deaths during this clinical study and no subjects discontinued from the study due to an AE.

Table 3. Incidence and severity of treatment-emergent AEs in the SAF
  ASKP1240 treatment groups 
AEsPlacebo (N = 36)0.1 mg/kg (N = 6)0.3 mg/kg (N = 6)1 mg/kg (N = 6)3 mg/kg (N = 6)10 mg/kg (N = 6)ASKP1240 total (N = 72)a
  1. a

    Includes all subjects randomized to the 12 ASKP1240 dose levels (i.e. 0.00003–10 mg/kg).

No. AEs reported3955681588
Subjects with AEs, N (%)17 (47.2)2 (33.3)3 (50.0)3 (50.0)4 (66.7)6 (100)38 (52.8)
No. drug-related AEs133455638
Subjects with drug-related AEs, N (%)8 (22.2)1 (16.7)2 (33.3)3 (50.0)2 (33.3)3 (50.0)18 (25.0)
No. serious AEs1000000
Subjects with serious AEs, N(%)1 (2.8)000000
Subjects with AEs by severity, N (%)
 Mild16 (44.4)2 (33.3)3 (50)2 (33.3)3 (50.0)5 (83.3)34 (47.2)
 Moderate1 (2.8)001 (16.7)1 (16.7)03 (4.2)
 Severe000001 (16.7)1 (1.4)
Table 4. Type of treatment emergent AEs reported by ≥2 recipients of ASKP1240 in the safety analysis set
  ASKP1240 treatment groups 
MedDRA preferred termPlacebo (N = 36)0.1 mg/kg (N = 6)0.3 mg/kg (N = 6)1 mg/kg (N = 6)3 mg/kg (N = 6)10 mg/kg (N = 6)ASKP1240 total (N = 72)a
  1. a

    Includes all subjects randomized to the 12 ASKP1240 dose levels (i.e. 0.00003–10 mg/kg).

Headache4 (11.1)0001 (16.7)3 (50.0)7 (9.7)
Upper respiratory infection1 (2.8)0003 (50.0)06 (8.3)
Cough1 (2.8)1 (16.7)00005 (6.9)
Dermatitis contact2 (5.6)1 (16.7)1 (16.7)0003 (4.2)
Dizziness1 (2.8)00001 (16.7)3 (4.2)
Back pain0001 (16.7)002 (2.8)
Diarrhea001 (16.7)0002 (2.8)
Feeling hot0000002 (2.8)
Flatulence1 (2.8)01 (16.7)001 (16.7)2 (2.8)
Infusion site pain0000002 (2.8)
Medical device site reaction01 (16.7)00002 (2.8)
Nausea1 (2.8)001 (16.7)01 (16.7)2 (2.8)
Pruritus001 (16.7)0002 (2.8)
Rhinorrhea0000002 (2.8)
Vessel puncture/site hematoma1 (2.8)000002 (2.8)
Vomiting0001 (16.7)002 (2.8)

Mean values for vital signs and serum biochemistry remained within reference ranges through the study. While individual subjects did have hematology values above and below the reference ranges throughout the study, no trend with dose increase was noted and no value was reported as an AE.

Coagulation and thrombotic parameters were monitored extensively throughout this study. Platelet function (adhesion/aggregation) after stimulation with adenosine diphosphate and epinephrine (PFA-100 closure) varied over time but no trends were observed either within or between treatment groups. Minor, clinically insignificant, fluctuations in E-selectin (CD62E) and MAC-1 values were observed throughout the study, indicating a lack of endothelial cell and monocyte activation. Importantly, both individual and mean cytokine measurements remained low in all treatment groups and no dose-related changes were observed. There was no clinical evidence of cytokine release syndrome or thromboembolic events.

Immunogenicity

None of the 36 subjects who received placebo were positive for anti-ASKP1240 antibody either predose or postdose. In the ASKP1240 treatment groups, two subjects tested positive for anti-ASKP1240 antibody predose (in the 0.01 and 10 mg/kg groups). Titers decreased from eight at baseline to five at day 43 in the subject belonging to the 0.01 mg/kg group, whereas titers of one were detected at baseline and at day 60 in the subject belonging to the 10 mg/kg group (this subject was seronegative on day 7 and day 15). Five ASKP1240-treated subjects who were negative at baseline seroconverted (four subjects were in the 1 mg/kg group and 1 subject was in the 10 mg/kg group). The timing of first seroconversion ranged from day 29 to day 75 in these five subjects; titers ranged from 2 to 48. All five subjects who seroconverted during the study were positive for a neutralizing anti-ASKP1240 antibody.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

This trial represents the first administration to humans of ASKP1240, a fully human antagonist anti-CD40 IgG4 monoclonal antibody. ASKP1240 was well tolerated at all doses, with the most common treatment-emergent AEs being headache, upper respiratory tract infection and cough. ASKP1240 administration was not associated with cytokine release syndrome, thromboembolic events, or activation of T cells, platelets or endothelial cells. In previous attempts to block the CD40-CD40L interaction using anti-CD40L monoclonal antibodies (hu5C8, IDEC-131 and ABI793) clinical development was complicated by thromboembolic events [8-11]. As ASKP1240 may not be associated with such complications, the CD40-CD40L interaction remains an attractive target for costimulation blockade.

ASKP1240 showed nonlinear PKs with higher clearance and shorter elimination half-life values at lower doses. This is often indicative of target mediated drug disposition [12]. As dose increases, the CD40 receptors are saturated and the clearance mediated by specific target binding was decreased. Pharmacodynamically, ASKP1240 demonstrated dose-dependent B cell CD40 receptor occupancy. Mean maximal receptor occupancy was reached at doses of 0.01 mg/kg and above. As doses increased above 0.01 mg/kg, the duration of receptor occupancy was prolonged in a dose-dependent manner. Although the fate of bound ASKP1240 is unknown, another antagonistic anti-CD40 monoclonal antibody is not internalized on binding to CD40 [13].

ASKP1240 did not alter total lymphocyte counts or lymphocyte subsets. Other antagonistic anti-CD40 agents similar to ASKP1240 have demonstrated depletion of CD19 positive cells [14-16]. The administration of agonistic CD40 monoclonal antibodies has also been performed clinically [17]. Following the administration of an agonistic anti-CD40 IgG2 to patients with various advanced solid organ tumors, lymphocytopenia (along with thrombocytopenia and dose-related transient elevations in serum liver transaminases) were observed [17]. Of note, mild and reversible cytokine release syndrome occurred in 16 of 29 patients [17].

Although 7 of 72 ASKP1240 recipients (9.7%) were identified as having a treatment emergent anti-ASKP1240 antibody in this current study, two subjects had positive antibody results prior to and following treatment. In the five subjects who seroconverted during the study, human against human antibody titers (HAHA) were low. Neutralizing anti-ASKP1240 antibody titers were detected in these same five subjects, the clinical significance of which remains to be determined.

In conclusion, this is the first study to evaluate the PK, PD, and safety of ASKP1240 in healthy subjects. The data provides initial evidence that the CD40-CD40L interaction can be blocked without inducing serious adverse events. The findings support further clinical development of ASKP1240, which will establish the role and optimal dosage regimen for ASKP1240 in solid organ transplant patient populations.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

The authors sincerely thank all subjects participating in this study. Kyowa Hakko Kirin Co., Ltd. kindly supplied ASKP1240 and Amit Desai kindly provided the non-compartmental PK parameters. Editorial support, including writing assistance with draft development, was provided by Malcolm Darkes and Michelle Seymour, both professional medical writers from UBC-Envision Group.

Funding source: Astellas Pharma Global Development, Inc and Kyowa Hakko Kirin Co., Ltd.

Statistical analyses were supported by Astellas Pharma Global Development, Inc.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. J. Keirns, P. Blahunka, R. First, T. Sawamoto, W. Zhang, D. Kowalski, A. Kaibara and J. Holman are full-time employees of Astellas Pharma Global Development. Dr. Goldwater is an employee of PAREXEL International, who were contracted by Astellas Pharma Global Development, Inc to perform the study.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References
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