(Circulation. 1999;100:2499.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
From the Departments of Anesthesiology (J.C.K.F., R.H., P.K., C.R.), Laboratory Medicine (C.R., H.R., B.S.), and Cardiothoracic Surgery (M.D., J.E., G.K., R.S.), Yale University, New Haven, Conn; Department of Anesthesiology (C.D.C., G.S., S.K.S.) and Cardiac Surgery (S.A.), Brigham and Womens Hospital, Boston, Mass; Biopure Corporation (B.A.), Boston, Mass; Department of Psychiatry, Stanford University (R.O.), Palo Alto, Calif; and Alexion Pharmaceuticals (S.R., L.M., L.L.), New Haven, Conn. Alexion Pharmaceuticals manufactures h5G1.1-scFv, the drug that was studied in this investigation.
Correspondence to Jane C.K. Fitch, MD, Department of Anesthesiology, Baylor College of Medicine, 6550 Fannin, Suite 1003, Houston, TX 77030. E-mail jfitch{at}bcm.tmc.edu
| Abstract |
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Methods and ResultsA humanized, recombinant, single-chain antibody specific for human C5, h5G1.1-scFv, was intravenously administered in 1 of 4 doses ranging from 0.2 to 2.0 mg/kg before CPB. h5G1.1-scFv was found to be safe and well tolerated. Pharmacokinetic analysis revealed a sustained half-life from 7.0 to 14.5 hours. Pharmacodynamic analysis demonstrated significant dose-dependent inhibition of complement hemolytic activity for up to 14 hours at 2 mg/kg. The generation of proinflammatory complement byproducts (sC5b-9) was effectively inhibited in a dose-dependent fashion. Leukocyte activation, as measured by surface expression of CD11b, was reduced (P<0.05) in patients who received 1 and 2 mg/kg. There was a 40% reduction in myocardial injury (creatine kinaseMB release, P=0.05) in patients who received 2 mg/kg. Sequential Mini-Mental State Examinations (MMSE) demonstrated an 80% reduction in new cognitive deficits (P<0.05) in patients treated with 2 mg/kg. Finally, there was a 1-U reduction in postoperative blood loss (P<0.05) in patients who received 1 or 2 mg/kg.
ConclusionsA single-chain antibody specific for human C5 is a safe and effective inhibitor of pathological complement activation in patients undergoing CPB. In addition to significantly reducing sC5b-9 formation and leukocyte CD11b expression, C5 inhibition significantly attenuates postoperative myocardial injury, cognitive deficits, and blood loss. These data suggest that C5 inhibition may represent a novel therapeutic strategy for preventing complement-mediated inflammation and tissue injury.
Key Words: cardiopulmonary bypass inflammation proteins immunology
| Introduction |
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Clinical manifestations attributed to this systemic inflammatory response involve morbidity to multiple organ systems, including the heart, brain, blood, lung, kidney, and gastrointestinal tract.1 4 8 Myocardial injury may manifest as perioperative Q-wave or nonQ-wave myocardial infarction (MI) or as severe ventricular dysfunction requiring circulatory assist.1 Systemic inflammation, together with diffuse cerebral microembolization,9 may result in clinically significant stroke or, more commonly, in cognitive deficits that persist in a significant proportion of patients.9 10 Additional clinical sequelae of CPB-induced inflammation and ischemia include impaired hemostasis, pulmonary edema, renal insufficiency, and gastrointestinal dysfunction.4 11
Among the inflammatory cascades, activated components of the complement system contribute to all phases of the inflammatory response.12 In particular, the products that are generated after cleavage of C5, namely, C5a and C5b-9, are potent inflammatory mediators with pleiotropic activities that include alteration of blood vessel permeability and tone, leukocyte chemotaxis, and activation of multiple inflammatory cell types.12 The generation of these byproducts during CPB is well documented and has been shown to correlate with clinical morbidity.13 14 15 Inhibition of complement activation at C5 would prevent the formation of these proinflammatory molecules while allowing the generation of upstream products, such as C3b, the critical mediator of bacterial opsonization as well as immune complex solubilization and clearance. C5 inhibition therefore represents a potentially effective therapeutic modality for reducing CPB-induced inflammation.
Using a novel approach to complement inhibition, we have developed a
25-kDa recombinant, humanized, single-chain antibody (h5G1.1-scFv) that
binds to human C5 with very high affinity (
100 pmol/L) and thereby
blocks C5 cleavage by both the classic and alternative complement
pathway C5 convertases.16 In preclinical studies,
antibody-mediated C5 inhibition markedly reduced inflammation and
tissue damage in models of bypass-associated
bioincompatibility,17 myocardial ischemia, and
reperfusion.18 This investigation reports the first
clinical studies examining the safety, pharmacology, and initial
biological and clinical efficacy of the h5G1.1-scFv C5
inhibitor in patients undergoing CABG surgery with
CPB.
| Methods |
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The study was performed in 2 phases. In phase 1, 17 patients were randomly assigned to 1 of 4 groups (n=4) receiving 0.2, 0.5, 1.0, or 2.0 mg/kg of h5G1.1-scFv. In each group, 1 patient randomly received placebo. In phase 2, 18 patients were randomly assigned to 3 groups (n=6) receiving placebo or 1.0 or 2.0 mg/kg h5G1.1-scFv.
Study Procedures
All potential patients were screened before enrollment. Once all
inclusion and exclusion criteria were satisfied, patients were
randomized. Perioperative testing included medical
history and physical examination, laboratory testing (hematology,
chemistry, and urinalysis), ECG, and Mini-Mental State Examination
(MMSE). Data collection included chest-tube output and transfusion
requirements.
Systemic heparin was administered before CPB. Once the activated clotting time was greater than 400 seconds, h5G1.1-scFv was infused over a 10-minute period, followed by initiation of CPB. Although the conduct of anesthesia and surgery was similar for each institution, no attempts were made to standardize techniques. CPB was conducted with hemodilution, moderate hypothermia, and membrane oxygenators.
After surgery, patients were transported to the intensive care unit for 24 to 48 hours and then transferred to a telemetry unit until hospital discharge. Patients were seen 4 to 6 weeks after surgery for a termination interview and blood sampling.
Blood-Sample Collection
Blood samples were drawn before, during, and after CPB at
predetermined intervals: before heparinization, 5 minutes after
administration of h5G1.1-scFv, after 5 minutes at 28°C, after
initiation of rewarming, after 5 minutes at 37°C, after CPB (5
minutes and 2, 7, 12, 18, 24, 36, and 48 hours after CPB), at hospital
discharge, and 4 to 6 weeks after surgery. All samples were immediately
centrifuged at 4°C and stored at -70°C until they were
assayed.
h5G1.1-scFv Study Drug
The study drug h5G1.1-scFv (Alexion Pharmaceuticals, Inc, New
Haven, Conn) is a recombinant, fully humanized, single-chain
antibody with picomolar affinity for a sequence within human
C5.16 It was supplied as a sterile, nonpyrogenic solution
(2 mg/mL) for intravenous injection.
Monoclonal Antibodies
h5G1.1-scFv was produced as a recombinant protein in
Escherichia coli and purified under GMP conditions as
described previously.16 Anti-CD45 (2D1,
Becton-Dickinson) and anti-CD11b (F6.2, Exalpha) were used for
leukocyte labeling.
Biological Assays
Pharmacokinetics of h5G1.1-scFv were determined by a double
sandwich ELISA (NUNC). This assay detects both free and C5-bound
h5G1.1-scFv and thus reflects the total h5G1.1-scFv in the serum.
Briefly, ELISA plates were coated with rabbit anti-mouse IgG1 antibody
(Zymed) and then blocked with PBS containing Tween 20 (Sigma). After
they were washed, the plates were incubated with mouse
antih5G1.1-scFv (6A8). Serum samples were added and incubated. After
the final washing was performed, anti-mouse IgG2b (7H7) antibody was
added, and the plates were developed with peroxidase substrate (Zymed).
Total serum complement hemolytic assays (pharmacodynamics) were
performed as described previously.17 For measurement of
fluid-phase C3a (C3a des-arg) and sC5b-9, serum was diluted in sample
preservative solution (Quidel) immediately before freezing, then
determinations were made as described previously.17
Creatine KinaseMB Assay
Myocardial-specific isoforms of creatine kinase (CK) were
measured in the clinical laboratories of the 2 hospitals by a standard
technique.
Fluorescence Labeling of Leukocytes and Flow
Cytometry
Whole-blood samples were immediately fixed in
paraformaldehyde PBS for flow cytometry
studies.17 Samples were prepared for labeling, incubated
with saturating concentrations of mAb, and then prepared for
fluorescence-activated cell sorter (FACS)
analysis as previously detailed.17 Samples were
analyzed on a FACScan flow cytometer (Becton-Dickinson). For
determination of leukocyte activation, samples were labeled with
FITC-anti-CD45 or PE-anti-CD11b. Leukocyte measurements were performed
by live gating on FITC-positive, leukocyte-sized events with forward-
versus side-scatter parameters used to differentiate
between monocyte and neutrophil subsets.
Cognitive Function Testing
The MMSE19 was administered by a single individual
at each site to each patient at screening, on postoperative day 1, and
at hospital discharge. The MMSE was used to quantify global cognitive
function. However, the measured degree of cognitive decline in this and
other studies is influenced not only by intervention but also by the
sensitivity and specificity of the tests used.20
Statistical Analysis
All data are presented as mean±SEM. Statistical
analysis (True Epistat version 5.1, EpiStat and InStat version
3.01, GraphPad) was performed by multivariate ANOVA for
repeated measurements over time and a 1-way ANOVA with Tukeys
multiple comparison procedure for continuous variables. Categorical
variables, including cognitive deficits, were analyzed by
2 analysis or Fishers exact tests.
Statistical significance was defined as a P value
<0.05.
| Results |
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Pharmacokinetics and Biodistribution
Previous studies on the pharmacokinetics of single-chain
antibodies have demonstrated rapid clearance from the serum, with serum
half-lives (t1/2) ranging from 15 to 30
minutes.21 The pharmacokinetic profile of h5G1.1-scFv was
determined from serum levels after a single bolus administration before
CPB. A dose-dependent increase in serum levels of h5G1.1-scFv persisted
throughout the 26-hour monitoring period (Figure 1
A), and a biphasic decline was noted at all
doses. h5G1.1-scFv was not detected in any serum sample collected 5 to
7 days after drug administration (data not shown). The initial
deposition phase for all doses occurred within 4 hours of
administration and was followed by a prolonged terminal elimination
phase. The t1/2 was decreased at lower doses of
h5G1.1-scFv (7.0 to 8.9 hours) compared with the 2.0 mg/kg dose (14.5
hours). This substantial prolongation in the t1/2 of
h5G1.1-scFv relative to other single-chain antibodies is most likely
due to its high affinity binding to (Kd=100
pmol/L) and slow dissociation rate from
(Koff=1.0x10-4/s)
the 190-kDa human C5 protein.16
|
Biodistribution of h5G1.1-scFv was determined for the 1.0 and 2.0 mg/kg
doses (Figure 1B
) 4 hours after administration. There was no
significant difference in the renal clearance of h5G1.1-scFv at either
dose. There was, however, a dose-dependent increase in the
intravascular distribution (37.1 versus 51.5 mg) and a 4-fold increase
in the extravascular distribution (26.8 versus 106 mg) of h5G1.1-scFv.
The pharmacokinetic profile of the 2.0 mg/kg dose suggests that the
prolonged t1/2 of h5G1.1-scFv (14.5 hours) resulted
from a return of the extravascular pool of drug into the intravascular
space during the 26-hour monitoring period.
Pharmacodynamics
Serum complement hemolytic activity was measured to assess
the efficacy of h5G1.1-scFvmediated complement inhibition. Our
previous studies16 have shown that h5G1.1-scFv binds to C5
in serum, resulting in a dose-dependent inhibition of total serum
hemolytic activity. Serum complement hemolytic activity
(pharmacodynamics) was not significantly inhibited in patients who
received 0.2 mg/kg h5G1.1-scFv. However, hemolytic activity was
significantly (P<0.05) inhibited in a dose-dependent
fashion by all remaining doses of h5G1.1-scFv compared with placebo
(Figure 2
C). Hemolytic activity dropped
markedly 5 minutes after administration of 0.5 mg/kg h5G1.1-scFv and
gradually returned to normal over a 12-hour period. Administration of
h5G1.1-scFv at the 1.0 and 2.0 mg/kg doses completely inhibited
hemolytic activity for >2 hours after CPB. In addition, the 2.0 mg/kg
dose substantially reduced (>50%) hemolytic activity for >14 hours.
The pharmacodynamic profile of the 2.0 mg/kg dose was
consistent with the pharmacokinetic analysis, which
demonstrated a substantial difference in serum levels 12 hours after
CPB (Figure 1A
).
|
Analysis of Complement Activation
Serum C3a and sC5b-9 levels were measured to demonstrate the
effect of h5G1.1-scFv on the generation of activated complement
components. C3a levels did not significantly differ between patients
who received placebo and those who received h5G1.1-scFv (Figure 2A
). In contrast, sC5b-9 levels were significantly
(P<0.05) decreased in a dose-dependent manner in patients
treated with h5G1.1-scFv (50%, 90%, >99%, and >99% for the 0.2,
0.5, 1.0, and 2.0 mg/kg doses, respectively) compared with placebo
(Figure 2B
).
Analysis of Leukocyte Activation
CD11b expression was measured on activated neutrophils and
monocytes (Figure 3
A and 3B). In doses
sufficient to completely block hemolytic activity and sC5b-9 generation
(1.0 and 2.0 mg/kg), h5G1.1-scFv significantly (P<0.05)
attenuated peak leukocyte CD11b expression compared with placebo.
|
Analysis of Myocardial Injury
Soluble C5b-9 production22 correlates with
myocardial injury during CPB.23 24 25 To assess myocardial
injury, the total release of CK-MB was measured during the 24 hours
after drug administration. Total CK-MB was significantly less
(P<0.05) in patients treated with 2.0 mg/kg h5G1.1-scFv
than in those given placebo (704±166 versus 1245±449 IU/mL; Figure 4
).
|
Cognitive Deficits
Preoperative and postoperative cognitive performance
were assessed with the MMSE (Figure 5
). Compared with preoperative scores for all
patient groups, cognitive performance on the MMSE was
significantly worse on postoperative day 1 (P<0.041) but
not on postoperative days 5 to 7 (P<0.01). However, none of
the patients treated with 2.0 mg/kg h5G1.1-scFv demonstrated new
language deficits on postoperative days 5 to 7 compared with 44% of
patients who received placebo (P<0.05; data not shown).
Furthermore, significantly fewer patients treated with 2.0 mg/kg
h5G1.1-scFv experienced new postoperative visuospatial
reproduction deficits on postoperative days 5 to 7 (11% versus
55% of those who received placebo; P<0.035).
|
Postoperative Blood Loss
Postoperative chest-tube output was collected to assess the
effect of h5G1.1-scFv on blood loss. Chest-tube output was
significantly less (P<0.05) in patients treated with 1.0 or
2.0 mg/kg h5G1.1-scFv (962±133 or 1087±209 mL) than in those given
placebo (1474±101 mL). In this small population, there were no
differences in transfusions among groups.
| Discussion |
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There is substantial evidence that activated components of the complement system play a central role in CPB-associated inflammation and tissue injury. First, elevated levels of activated complement byproducts can be detected in patients undergoing CPB and have been found to correlate with morbidity and mortality.14 15 Second, the byproducts of C5 complement cleavage, C5a and C5b-9, possess multifaceted proinflammatory properties that contribute to tissue injury in the setting of CPB.12 C5a is a potent anaphylatoxin, vasoconstrictor,26 and chemotactic factor for leukocytes.27 Both C5a and C5b-9 promote leukocyte/endothelial cell interaction via the upregulation of adhesion molecules, such as selectins and the integrin MAC-1 (CD11b/CD18), and alter blood vessel integrity and hemostasis. Both C5a and C5b-9 also amplify inflammatory responses by stimulating cells to release additional inflammatory mediators.12 Finally, C5b-9 can mediate tissue injury directly because of its lytic properties.12
In addition to having intrinsic proinflammatory properties, activated complement byproducts also interact with components of other inflammatory pathways. Thus, contact system proteins (factor XIIa and kallikrein) and products of the coagulation cascade (thrombin and plasmin) have been reported to directly activate complement.2 3 4 The products of these other humoral pathways may also amplify complement-mediated activation of leukocytes and platelets.2 3 4 Finally, complement proteins can act synergistically with a number of cytokines in promoting inflammatory responses, as exemplified by the C5 dependence of tumor necrosis factor elaboration.28 29
There is substantial preclinical evidence to support a critical role for complement in mediating inflammation and tissue injury associated with the CPB-induced inflammatory response. Ex vivo recirculation of whole blood in an extracorporeal closed-loop bypass circuit has been studied extensively as a model to reconstruct the bioincompatibility-induced complement and leukocyte activation that occurs during CPB.17 The addition of inhibitory anti-C5 antibodies to this circuit completely blocked the generation of C5a and C5b-9, as well as the upregulation of leukocyte CD11b expression. These studies established that activation products of C5 cleavage, rather than upstream components of the complement cascade (C3a), are the predominant mediators of leukocyte activation in this model.
Studies have further established complement as an important mediator of inflammation and tissue injury secondary to ischemia and reperfusion.30 It has recently been shown that C5a is responsible for nearly 90% of chemotactic activity in cardiac lymph in the first 4 hours after reperfusion of canine myocardium.31 We18 have recently shown in a rodent model of myocardial ischemia and reperfusion that C5a and C5b-9 are key mediators of inflammation and tissue injury in myocardial ischemia and reperfusion. Administration of an anti-C5 mAb before myocardial ischemia and reperfusion dramatically reduced neutrophil infiltration, loss of high-energy phosphate stores, and infarct size.
These preclinical findings provided a firm rationale for the therapeutic trials of the recombinant, single-chain antibody C5 inhibitor in patients undergoing CPB. In the present study, h5G1.1-scFv proved to be a potent inhibitor of systemic complement activation, inhibiting both complement-dependent hemolytic activity and, more importantly, the generation of the proinflammatory activation product C5b-9. Consistent with all preclinical data, this potent complement inhibitory activity was associated with a significant anti-inflammatory effect, as illustrated by the significant inhibition of leukocyte CD11b upregulation achieved in the higher-dose treatment groups. Most importantly, the potent complement inhibitory and anti-inflammatory activities of h5G1.1-scFv were associated with significant reductions in postoperative CK-MB release, new cognitive deficits, and blood loss.
In the present study, the potent inhibitory and anti-inflammatory effects of h5G1.1-scFv were associated with significant reductions in postoperative myocardial injury. The reported incidence of MI after CABG surgery ranges from 1% to 10%.23 Mechanisms for MI after CABG are likely multifactorial and include preoperative, intraoperative, and postoperative ischemic times, postoperative reperfusion, systemic inflammation, and inadequate revascularization.23 24 25 According to postmortem studies,32 33 80% to 92% of post-CABG MIs occur without clinical evidence of transmural infarction. Elevated postoperative CK-MB levels are associated with an increasing incidence of postoperative ventricular regional wall motion abnormalities34 and decreased global left ventricular ejection fraction in the early post-CABG period,34 35 which can persist for up to 9 months regardless of the presence of Q waves on ECG.36 There does not appear to be a threshold effect, but rather, it is apparent that the greater the release of CK-MB, the greater the subsequent morbidity, cost, and mortality.37 38 39 40 Hence, it is likely that significant reductions in postoperative myocardial injury might be associated with improved outcomes. The more potent effect of the 2.0 mg/kg dose of h5G1.1-scFv may be related to the longer pharmacodynamic effect, which extends to 12 hours after CPB, because previous investigators have noted that most postoperative ischemic events occur in the first 10 hours after CPB.41 Single-chain antibodies have been shown to penetrate tissue more rapidly in vivo than their whole-antibody counterparts, and thus, the myoprotective effect of h5G1.1-scFv may have been related to its capacity for rapid tissue penetration.
Compared with patients who received placebo, those treated with h5G1.1-scFv experienced fewer cognitive deficits. C5 inhibition has similarly been shown to reduce cerebral edema and infarct volume in a rodent model of central nervous system ischemia and reperfusion (S. Rollins, PhD, unpublished data, 1998). The spectrum of central nervous system morbidities after CPB includes cognitive dysfunction, encephalopathy, stroke, and brain death.20 42 Cognitive dysfunction is the most prevalent and subtle manifestation of central nervous system morbidity, occurring in 30% to 75% of patients after CPB and in up to 40% of patients 2 months after discharge.43 44 45 46 The cause of the cognitive decline is believed to be related to multifocal ischemic and/or hypoxic insults to the brain, leading to neuronal loss.47 48 49 50 51
In the present investigation, the cognitive measure used was the MMSE, which assesses global cognitive function. However, despite the constraints of a small sample size and the sensitivity/specificity of the MMSE, the observation that significantly fewer patients treated with the 2 mg/kg dose of h5G1.1-scFv exhibited visuospatial deficits and language deficits on postoperative days 5 to 7 than the placebo group suggests that h5G1.1-scFv may have the potential to ameliorate post-CPB cognitive decline and warrants further investigation.
Blood loss and the subsequent need for transfusion remain a significant complication of CPB. Recent efforts with antifibrinolytic agents have demonstrated reductions in blood loss, but concerns have been raised regarding prothrombotic complications.52 Reduction of complement activation via heparin coating of oxygenators and tubing has been associated with moderate decreases in blood loss.53 Furthermore, a correlation has been shown between the degree of complement activation and the amount of postoperative blood loss.54 Administration of h5G1.1-scFv was associated with a significant reduction in postoperative chest-tube output. Because h5G1.1-scFv does not affect the normal homeostatic regulation of coagulation cascade components, it would not be expected to promote a prothrombotic state.
In summary, we have shown that a humanized, single-chain antibody specific for human C5 is a safe and effective inhibitor of pathological complement activation in patients undergoing CPB. C5 inhibition in patients undergoing CPB produced a pronounced anti-inflammatory effect and was associated with significant reductions in myocardial injury, new cognitive deficits, and blood loss. This provides preliminary evidence that complement inhibition at C5 may reduce clinical morbidity associated with CPB. The clinical findings must be interpreted as preliminary in view of the small number of patients assigned to each treatment group, and they await confirmation in larger studies. The results of this study may also have implications for the use of the single-chain C5 complement inhibitor in other clinical settings associated with inflammation secondary to tissue ischemia and reperfusion, such as MI or stroke with thrombolytic therapy, and in percutaneous angioplasty procedures.
| Acknowledgments |
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Received March 11, 1999; revision received July 28, 1999; accepted August 4, 1999.
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