1 2nd Medical Department/SMZ Baumgartner Höhe, Mantlergasse 23/2/12, A-1130 Vienna; 2 Institute of Applied Microbiology, Vienna; 3 Polymun Scientific Immunobiological Research GmbH, Vienna; 4 Institute of Pharmaceutical Chemistry, University of Vienna, Vienna; 5 Institute of Medical and Chemical Laboratory Diagnostics, KH Lainz, Vienna; 6 Institute of Hygiene and Social Medicine, University of Innsbruck, Innsbruck, Austria
Received 30 April 2004; returned 29 July 2004; revised 31 July 2004; accepted 14 August 2004
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Abstract |
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Materials and methods: Eight healthy volunteers with 350 CD4 cells/mm3 and
100 000 HIV-1 RNA copies/mL were enrolled, seven finished the study. A single 4E10 infusion was administered on day 0, followed by three doses of the hMAb combination 4E10/2F5/2G12 on days 7, 14 and 21 (total amount 8.5 g). Safety was assessed by physical examination, blood chemistry, complete blood cell count and recording of adverse events. 4E10, 2F5 and 2G12 plasma levels were determined before and at the end of each infusion and during the 7 week follow-up.
Results: No drug-related adverse events were observed throughout the study. The median plasma concentrations immediately after the first infusion were 371, 253 and 139 µg/mL for 4E10, 2F5 and 2G12. Multiple infusions resulted in maximum plasma concentrations of 407, 294 and 210 µg/mL for 4E10, 2F5, and 2G12, respectively. The median elimination half-lives (tß) were 6.6, 3.2 and 14.1 days for 4E10, 2F5 and 2G12. A low level antibody response against 2G12 was found in two patients.
Conclusion: This Phase I trial showed that the hMAb 4E10 can be safely administered, both alone and in combination with 2F5 and 2G12 to HIV-1-infected patients.
Keywords: human neutralizing monoclonal antibodies , pharmacokinetics , safety , HIV infection
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Introduction |
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During the last decade, several human monoclonal antibodies of exceptional antiviral capacity potently neutralizing primary isolates of different clades have been established.6,7 Among these, the three investigational antibodies 4E10, 2F5 and 2G12 have been shown to be effective not only in vitro but also in the animal model.810 4E10 recognizes the linear epitope NWFDIT adjacent to the 2F5 binding region EQELLELDKWASLW on the ectodomain of the HIV-1 envelope gp41. 2G12 is directed against carbohydrates on a conformation-dependent epitope of gp120.1114
Recently, 2F5 and 2G12 were tested in a first Phase I open-label trial.15 This study showed that both antibodies were safe, non-toxic and not immunogenic. Moreover, analysis of preliminary effects on markers of disease progression showed encouraging results. Nevertheless experience from the last decade with anti-HIV therapy demonstrated that HIV is able to develop resistance against all currently approved drugs.3 For that reason it is necessary to combine several drugs to reduce the possibility of virus escape.
Our work aimed to supplement the hMAb combination 2F5/2G12 with the third antibody 4E10 to increase the antiviral effect and reduce the likelihood of neutralization escape.
In the present report, we describe the results of the first Phase I trial with 4E10 conducted to determine safety, immunogenicity and pharmacokinetics in asymptomatic HIV-1-infected adults. A further objective was to evaluate the safety and pharmacokinetics of repeated intravenous doses of 4E10 in combination with 2F5 and 2G12. The triple drug regimen was chosen based on in vitro and animal studies demonstrating synergic effects with 2F5 and 2G12 in their neutralizing potency.8,9,16
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Materials and methods |
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Patients' screening CD4 cell counts and HIV-1 RNA copy numbers were required to be 350 cells/mm3 and
100 000 copies/mL, respectively. Subjects were
18 years of age, had a Karnofsky performance score of
70 and had adequate haematological, liver and renal function: serum aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase levels
3x the upper limit of normal; serum creatinine
1.5x the upper limit. Women of child-bearing potential had to have a negative ß-HCG pregnancy test directly before the first antibody infusion. Patients were excluded from the study in case of debilitating HIV disorders, active substance abuse, pregnancy, active opportunistic infections, malignancies and current immunomodulating therapies. Participants neither received concomitant antiretroviral therapy (ART) during the study period of 77 days nor at any time in the past.
Antibodies
Generation and characterization of 4E10, 2F5 and 2G12 were described previously.6,17,18 The hMAbs were produced by recombinant expression in CHO cells as IgG1(). All three antibodies contain identical constant regions and differ only in their variable regions, which were derived from the original hybridoma cells. Large-scale production was carried out in protein-free medium in 550 L suspension culture bioreactors. After a multiple step purification procedure, the hMAbs were filled aseptically into infusion bags (Stedim, Aubagne, France) as solutions ready for intravenous use. The concentration was approximately 12 mg/mL in a 2 mM acetic acid solution with 10% maltose.
MAb administration
Each infusion of 4E10 and 2F5 contained 1.0 g of the antibody, whereas the dose of 2G12 was reduced to 0.5 g based on the pharmacokinetic results of the first Phase I trial.15 For technical reasons a fixed amount of antibody was filled into the infusion bags rather than adjusting antibody doses to body weights. On day 0 participants received a single intravenous infusion of 4E10. On days 7, 14 and 21 after 4E10 the hMAbs 2G12 and 2F5 were applied.
The antibody infusions were adjusted to room temperature and infused at a low flow rate using a 0.2 µm infusion filter. The duration of each infusion was approximately 30 min. After the end of the infusion the flexible infusion tubes were flushed with physiological NaCl solution in order to avoid loss of hMAb. Treatment was carried out in a controlled environment with all necessary emergency equipment in place to treat possible side effects. Vital signs were recorded continuously. After the 4 week treatment period patients were followed-up until day 77 by physical examination, measurement of clinical laboratory parameters, HIV-1 RNA copy number and CD4 cell count.
Blood and urine sampling
Blood was drawn on all study days before and immediately after antibody infusions and during the follow-up period on days 28, 35, 49 and 77. Samples for general laboratory evaluations were obtained before antibody infusions. Urine samples were collected on days 0, 1, 7, 14, 21 and 28 for investigation of immune complex disease (ICD). Blood samples were collected by venepuncture and placed into 7 mL vacutainer tubes containing 0.34 M (15%) K3-EDTA. Samples were processed within 4 h of collection by centrifugation at 650 g. Plasma was removed for storage at 70°C. PBMC were collected by Ficoll gradient separation at 400 g.
Safety evaluation
The safety and tolerability of multiple 4E10, 2F5 and 2G12 doses were evaluated on the basis of recording adverse events, measurements of vital signs, clinical laboratory tests, physical examination and electrocardiograms.
In addition, CD4 cell counts and HIV-1 RNA copy numbers were measured by flow cytometry (FACS Prep, Becton Dickinson, San José, CA, USA) and polymerase chain reaction (Roche Amplicor HIV Monitor, version 1.5, ultrasensitive mode, Basle, Switzerland).
Immunogenicity of 4E10, 2F5 and 2G12
Immunogenicity was analysed by determination of anti-4E10, anti-2F5 and anti-2G12 IgM and IgG by a µ- and -specific double-sandwich ELISA as described previously.15
Formation of immune complexes
Development of immune complex disease (ICD) was evaluated by determination of plasma immune complexes containing 2G12 in a double-sandwich ELISA. Plates were coated overnight with 1 µg C1q/well. Plates were blocked with 3% skimmed milk before incubation with plasma samples diluted 1:50. After washing, the plates were incubated with anti-2G12 antibody M1G1*biotin. After washing again streptavidinß-galactosidase solution was added and after 20 min plates were finally developed with resorfurin-ß-D-galactopyranoside. Absorbance was measured at 550/620 nm. Concentrations of immune complexes in plasma were determined from standard curves generated from known concentrations of immune complexes achieved by incubation of 2G12 and rgp160 for 30 min at 56°C. The detection limit was 1 µg/mL.
4E10, 2F5 and 2G12 ELISA
Plasma 4E10 concentrations were measured before and at the end of each infusion on days 0, 7, 14 and 21 and on days 1, 2, 4, 28, 35, 49, and 77 by a 4E10-specific double-sandwich ELISA. Briefly, plates were coated overnight with the KKWNWFDITNWGGG peptide as capture antigen. Plates were washed and incubated with serial two-fold dilutions of plasma samples. After washing again plates were incubated with goat anti-human IgG (-specific) conjugated with horseradish peroxidase (POD). After further washing, POD substrate was added and the enzymic reaction leading to a coloured product was stopped with H2SO4 after several minutes. Absorbance was measured at 492/620 nm and results were calculated using 4th-parameter logistic for curve fitting. Concentrations of hMAbs in plasma were determined from standard curves generated from known concentrations of 4E10.
Investigations of plasma 2F5 and 2G12 concentrations were carried out before and at the end of each infusion on days 7, 14, 21, and on days 28, 35, 49 and 77 as described previously.15 The detection limit of the three ELISAs is 3 ng/mL.
Pharmacokinetic analysis
Pharmacokinetic analysis was carried out using the plasma concentrations of the hMAbs determined by ELISA. Parameters were calculated by non-compartmental analysis using WinNonlin (version 1.5, Scientific Consulting, USA) from individual plots of concentrations in plasma against time. Cmin and Cmax were observed values. The elimination half-lives (tß) of all hMAbs were calculated based on five plasma concentrations measured on study days 21, 28, 35, 49 and 77.
Virus isolation by co-culture and neutralization assay
Virus isolation was carried out as recommended.19 Viruses were isolated by co-cultivation of patient PBMC and IL-2-phytohaemagglutinin-stimulated donor PBMC as described previously.15 Presence of virus growth was determined by p24 in-house ELISA (detection limit, 1.5 pg p24/mL) of co-culture supernatant.20 Cryopreserved virus isolates were tested in standard PBMC neutralization assays for sensitivity to 4E10, 2F5, 2G12 and their combination.15 To determine virus resistance to neutralization of the hMAbs during the course of treatment, isolates obtained on days 14, 28 and 77 were analysed for neutralization by 4E10, 2F5, 2G12, and the triple combination additionally.
Statistical analysis
Results are shown as means ±S.D. and as median values with ranges in parentheses. Changes in viral loads are expressed in log10 transformation of absolute RNA copy numbers per mL. Patient characteristics and pharmacokinetic parameters were compared for significance of differences by Spearman's rank order correlation coefficients, two-tailed Pearson test and paired two-tailed Student's t-test, when appropriate. Significance was defined as P < 0.05.
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Results |
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Seven patients received the scheduled dose of 8.5 g of monoclonal antibodies. 4E10 was administered four times in weekly intervals, either alone (day 0) or in combination with 2F5 and 2G12 (days 7, 14 and 21). Infusions of 2.5 g hMAb (triple combination) and of the total amount of 8.5 g hMAb resulted in a median dose of 33.33 (range, 26.3236.76) mg/kg body weight and 113.33 (range, 89.47125.0) mg/kg body weight, respectively.
4E10, 2F5 and 2G12 were well tolerated at single (4E10) and at multiple doses. No drug-related adverse events occurred during the treatment and follow-up period. There was no unusual decline in CD4 cell count or increase in HIV-1 RNA copy numbers (Figure 1).
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Plasma and urine samples were examined for indications of ICD. Plasma was analysed for the content of immune complexes containing 2G12. This antibody has a longer half-life than 2F5 and 4E10. In addition, an anti-idiotypic antibody against 2G12 was available to detect 2G12 entrapped in antigenantibody complexes. In none of the plasma samples were detectable amounts found. As an additional parameter for development of ICD, protein levels in urine were analysed. No abnormal values were detected.
Plasma samples obtained before the first antibody infusion were examined against background antibody levels reactive in the 4E10, 2F5 and 2G12-specific ELISAs. All samples tested negative for the presence of autologous antibodies binding to the GGGLELDKWASL-peptide specific for 2F5 and to the anti-idiotype of 2G12. Low-level binding was found to the 4E10-specific peptide KKWNWFDITNWGGG but amounts were generally lower than 1 µg/mL.
The median plasma concentration immediately after the first infusion was 371 µg/mL (range, 263426 µg/mL) for 4E10 on day 0, 253 µg/mL (range, 193279 µg/mL) and 139 µg/mL (range, 116164 µg/mL) for 2F5 and 2G12 on day 7. Multiple infusions resulted in Cmax of 407 µg/mL (range, 340602 µg/mL), 294 µg/mL (range, 253394 µg/mL), and 210 µg/mL (range, 181216 µg/mL) for 4E10, 2F5 and 2G12, respectively. Levels found at the end of the study (day 77) were still present in analytically significant amounts (0.110 µg/mL) in 5/8, 3/7 and 7/7 patients for 4E10, 2F5 and 2G12. The hMAb plasma concentrations of the seven volunteers are shown in Figure 2(a.
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Before the first antibody infusion, viruses were isolated by co-culture of patient and HIV-negative donor PBMC and examined for their sensitivity to neutralization by the single antibodies 4E10, 2F5 and 2G12 and their triple combination. Virus growth was detected after 411 days of co-cultivation by p24-ELISA. Isolates were harvested and tested in a standard PBMC neutralization assay. Virus replication of all isolates was inhibited at least 50% by 4E10 and 2F5 at concentrations <50 µg/mL. In contrast, 2G12 neutralized only 5/8 viruses (Table 3); 99% neutralization was achieved for 7/8, 4/8, 3/8 and 7/8 isolates by 4E10, 2F5, 2G12 and the triple combination, respectively. Virus escapes showing complete resistance to 50 µg/mL 2G12 were observed in three participants (06, 09, 10) at the end of the study. These viruses however were still neutralized by the triple hMAb combination (data not shown).
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Discussion |
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Therefore, the aim of the study was to determine the safety, immunogenicity and pharmacokinetics of the hMAb 4E10 alone and in combination with 2F5 and 2G12 in HIV-1-infected humans.
The results of this study showed that 4E10 is safe and well tolerated, both as single agent and in combination with 2F5 and 2G12. The good tolerance of these hMAbs is of key importance as they will be used in high- and/or multiple dosing regimens. The lack of toxicity of 4E10, 2F5 and 2G12 in humans even after repeated doses can be attributed to their fully human origin. In contrast, the majority of monoclonal antibodies currently available for other diseases are derived from other species, limiting their application due to heterologous immune responses. In comparison to other studies evaluating antibodies of non-human origin we did not find anti-4E10 and anti-2F5 IgM and IgG immune responses even after repeated applications of high doses of the hMAbs.2123 In contrast to findings of the first study, transient anti-2G12 IgM levels were present in two participants on days 28 and/or 77.15 As the anti-2G12 immune responses were rather low and no accelerating clearance rate was observed their significance is questionable.
Another critical parameter of antibody therapy is induction of ICD, a possible side effect of passive immune therapy when high concentrations of antibodies and antigen form large immune complexes. The examination of plasma samples for immune complexes containing 2G12 showed no detectable levels. As there are no anti-idiotypic antibodies available to 2F5 and 4E10, detection of immune complexes containing 2F5 and 4E10 was impossible. Absence of 2G12-containing complexes led to the hypothesis that 2F5 and 4E10 may also be unproblematic. This was confirmed by results of examined urine samples, which were assayed for possible development of ICD by measuring protein levels. No elevated protein levels were detected during the treatment period.
CD4 cell counts showed no evidence of accelerated decline which is in agreement with the results of the study published previously.15 The HIV-1 RNA copy numbers did not vary significantly (>0.5 log10 RNA copies/mL) in almost all patients. Two subjects showed a decrease on days 21 and/or 28. Whether this effect is attributable to hMAb treatment is not yet clear. The antiviral effects of the antibodies on p24, infectious virus load, infection of PBMC and other disease parameters are currently under investigation.
Passive immunization studies in macaques and in human peripheral lymphocyte-severe combined immunodeficient mice suggest that neutralizing antibodies have to be present at a concentration causing >99% neutralization in vitro, to have any impact on virological parameters in vivo.24 These concentrations were achieved in plasma of all participants after the first and after multiple infusions of 4E10, 2F5 and 2G12 (data not shown).
The results of this multiple-dose pharmacokinetic study confirmed the pharmacokinetic pattern observed in the first study: 2F5 had a significantly shorter half-life than 2G12. However, whereas median tß of 2G12 (14.1 days) corresponded well to the results of the first trial, median t
ß of 2F5 was possibly due to large intersubject variability reduced to 3.2 days compared with 7.94 days previously.15 The mean t
ß of 2F5 of 6.1 days corresponded more closely to the previous finding. The median half-life of 4E10 was determined to be 6.6 days, which was between the half-lives of 2F5 and 2G12. The reason for the shorter half-life of 4E10 and 2F5 in comparison to 2G12 is unclear as the three antibodies have the same constant backbones, which usually determine the degradation rate.17,18 The most probable causes may be determinants of the variable parts or differences in antibody glycosylation patterns. IgG1 molecules carry N-linked oligosaccharides in the constant CH2 domain of the Fc part.25 These N-linked glycans are highly heterogeneous and depend on the expression and production system. Although all three antibodies were produced in CHO cells, subtle differences in production clones can lead to significant differences in the complex biantennary structure greatly influencing effector functions and half-life.25 The glycosylation pattern of the three antibodies is currently under investigation.
This Phase I study was designed to determine the safety, immunogenicity and pharmacokinetics of 4E10 in combination with 2F5 and 2G12. Additional studies are necessary to establish the usefulness of the hMAb combination in therapeutic and preventive application. Two Phase II trials evaluating the effects of the hMAbs during strategic treatment interruption of HAART are under way. The hypothesis that hMAb therapy may delay viral rebound and protect against loss of CD4 cells thereby prolonging the drug holiday from HAART is being tested. Another possible approach is that improved treatment efficacy can be achieved by combination of HAART and hMAbs as different sites of viral replication are targeted and immunological mechanisms are influenced.
However, the highest probability of success is passive immunization with 4E10, 2F5 and 2G12 in preventive settings. Single doses of 2F5 administered to chimpanzees challenged with high doses of a primary virus delayed significantly seroconversion in these animals.26 Infusions of 2F5 or 2G12 alone or in combination with other hAbs protected juvenile, adult and pregnant macaques and their neonates against intravenous, intravaginal, and oral challenge with SHIV.810 A recent study showed that addition of 4E10 to a 2F5/2G12 post-exposure prophylaxis cocktail resulted in a more potent protection compared with the previously investigated hMAb combination.27 This provides hope that 4E10, 2F5 and 2G12 will be protective against mother-to-child transmission and as post-exposure prophylaxis after accidental exposure to HIV-1-contaminated material. A Phase I study with infants born to HIV-infected mothers will be initiated shortly. If this study is going to show the effectiveness of these three antibodies against transmission of HIV-1 it would be the first definite in vivo proof that hMAbs are an essential determinant for the design of a preventive vaccine.
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Acknowledgements |
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Footnotes |
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