NZ722524A - Method for treating infectious diseases using a composition comprising plasma-derived immunoglobulin m (igm) - Google Patents
Method for treating infectious diseases using a composition comprising plasma-derived immunoglobulin m (igm)Info
- Publication number
- NZ722524A NZ722524A NZ722524A NZ72252416A NZ722524A NZ 722524 A NZ722524 A NZ 722524A NZ 722524 A NZ722524 A NZ 722524A NZ 72252416 A NZ72252416 A NZ 72252416A NZ 722524 A NZ722524 A NZ 722524A
- Authority
- NZ
- New Zealand
- Prior art keywords
- plasma
- composition
- igm
- derived igm
- patient
- Prior art date
Links
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- 210000002381 Plasma Anatomy 0.000 title claims abstract description 44
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Abstract
Compositions and methods of the present invention prevent, inhibit or reduce the toxic effects of proteins and toxins secreted from microbes. A method for neutralizing microbial protein products in a subject comprises administering a composition to the subject, said composition comprising plasma-derived IgM and optionally one or more excipients in a pharmaceutical carrier, wherein the composition is administered in an amount effective to neutralize the microbial protein products. ived IgM and optionally one or more excipients in a pharmaceutical carrier, wherein the composition is administered in an amount effective to neutralize the microbial protein products.
Description
METHOD FOR TREATING INFECTIOUS DISEASES USING A
COMPOSITION COMPRISING PLASMA-DERIVED IMMUNOGLOBULIN M
(IGM)
DESCRIPTION
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority to United States
Provisional Patent Application No. 62/201,910, filed
August 6, 2015, the contents of all of which are
specifically incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to a method for treating
infectious diseases comprising the administration to a
patient in need thereof of a composition containing
plasma-derived IgM. The present invention also relates to
a method for neutralizing secreted cytotoxic exotoxins
during active microbial infections comprising the
administration to a patient in need thereof of a
composition containing plasma-derived IgM.
BACKGROUND OF THE INVENTION
Microbial species can become highly deleterious to an
infected patient, if that individual cannot clear the
infection, or if the patient is unresponsive to treatment.
Infections can also become septic, spreading from an
infected organ into the blood stream. These septic
infections have a poor outcome for patients, generally
resulting in organ failure and death.
The problem is that most antibiotics target the live
microbes themselves to treat the infection. IgM has been
characterized as preventing the toxic septic aspects of
bacterial infections due to systemic effects of microbial
endotoxins. These endotoxins are components of the cell
wall (in-particular in Gram-negative bacteria). Neither of
these methods of treatment target or have been shown to
target microbial exotoxins, superantigens, or secreted
enzymes.
While it is well characterized that plasma-derived IgM can
bind to and prevent endotoxin-mediated toxicity towards a
patient, this does not address other proteins and toxins
that are actively secreted from microbes. The toxic
effects of endotoxins are typically a response to
bacterial death or lysis induced by antibiotics or the
immune system of the patient. These effects are separate
from the toxic events that are observed during a microbial
infection due to proteins, such as exotoxins, that are
actively secreted by the microbe. There remains a need for
compositions and methods that prevent, inhibit or reduce
the toxic effects of proteins and toxins secreted from
microbes, other than endotoxins.
SUMMARY OF THE INVENTION
The present invention is based on the findings of a
surprising neutralization effect of therapeutic doses of
plasma-derived IgM to neutralize the deleterious impact of
the secreted microbial proteins, such as secreted
cytotoxic exotoxins, during active microbial infections.
The present invention makes use of the specificity of
plasma-derived IgM towards microbial proteins. As
explained above, it is well known that IgM binds microbial
endotoxins, which are glycoproteins, and that this binding
makes use of the general binding of IgM towards
glycoproteins and carbohydrates.
In the prior art, several monoclonal antibodies have been
described, but are individually directed only to a single
antigenic target. Natural plasma-derived IgM, on the other
hand, contains a plethora of potential antigen binding
sites that can target many different antigens
simultaneously and thus do not rely on a single treatment
modality.
Furthermore, the present invention makes use of a source
of IgM derived from a waste stream of a standard blood
fractionation process, for example Grifols’ Gamunex
fractionation process.
Therefore, in a first aspect, the present invention refers
to a method for treating infectious diseases comprising
the administration to a patient in need thereof of a
composition containing plasma-derived IgM. Stated another
way, an embodiment of the present invention provides a
method for treating an infectious disease in a subject,
said method comprising administering a composition to said
subject, said composition comprising, consisting
essentially of, or consisting of plasma-derived IgM and
optionally one or more excipients in a pharmaceutical
carrier, wherein the composition is administered in an
amount effective to neutralize microbial protein products
in said patient.
In a second aspect, the present invention refers to a
method for neutralizing secreted cytotoxic exotoxins
during active microbial infections comprising the
administration to a patient in need thereof of a
composition containing plasma-derived IgM. Stated another
way, an embodiment of the present invention provides a
method for neutralizing microbial protein products in a
subject, said method comprising administering a
composition to said subject, said composition comprising,
consisting essentially of, or consisting of plasma-derived
IgM and optionally one or more excipients in a
pharmaceutical carrier, wherein the composition is
administered in an amount effective to neutralize said
microbial protein products.
Said cytotoxic exotoxins can be secreted by several
microorganisms such as Escherichia coli, Pseudomonas
aeruginosa, Staphylococcus aureus, Klebsiella pneumoniae,
Streptococcus pneumoniae, Clostridium difficile,
Clostridium botulinum, Aspergillus flavus and combinations
thereof.
Preferably, the composition containing plasma-derived IgM
is obtained from a waste stream of a standard
fractionation process. The plasma-derived IgM has a purity
of at least 70% (w/v), more preferably at least 90% (w/v),
and the most preferably at least 95% (w/v) .
Also preferably, the dose of plasma-derived IgM to be
administered ranges from 75 mg to 1g per kilogram of the
patient, preferably from 75 mg/kg to 600 mg/kg, more
preferably from 75 mg/kg to 300 mg/kg. The dose can be
administered on a daily, every other day, 3x/week or once
per week, regimen.
Optionally, the composition of plasma-derived IgM further
comprises other molecules selected from small molecule
antibiotics, natural or synthetic peptide antimicrobials,
or proteins with antimicrobial properties, or a
combination thereof.
Examples of small molecule antibiotics are vancomycin and
meropenem. An example of proteins with antimicrobial
properties is lactoferrin.
In the method of the present invention, the composition of
plasma-derived IgM can be used alone or in combination
with other therapeutics molecules selected from the group
consisting of therapeutic molecules, including anti-
inflammatory agents, and immunomodulators.
BRIEF DESCRIPTION OF THE DRAWINGS
Embodiments of the present invention will be described
below in reference to the following figures in which:
Figure 1 shows the immunoreactivity of IgM against P.
aeruginosa Exotoxin A. Absorbance OD readings at 450nm are
shown for a representative ELISA. The target antigen, P.
aeruginosa Exotoxin A (P.A. ExA), was coated on ELISA
plates. Pooled plasma or IgM purified from the Gammunex
process was used as sources of IgM. Various dilutions of
this sample were tested, as indicated, in PBS. Controls
are wells that have not been coated with antigen
(Uncoated). Standard deviations are shown for each bar.
Figures 2A and 2B show the neutralization of C. difficile
Toxin B cytotoxicity. Caco-2 cells (obtained from ATCC)
were cultured in the recommended proliferation media.
Cells were seeded in 96-well plates at 8000 cells per
well. 24 hours after initial plating, cells were treated
with various IgM preparations and/or Clostridium difficile
Toxin B as described in the figure legend. Data for the
relative number of cells are shown as RLU, as measured by
the Cell Titer Glow (Promega Corp. Madison, WI, USA) assay
performed according to the manufacturer’s instructions.
Figure 2A demonstrates specificity of neutralization of C.
difficile Toxin B (Tox B) by a two different batches of an
IgG and IgM mixture (Frac. Conc. 45% and 70-80% IgM for
solid black bars and hatched bars, respectively, but not
for the non-specific control, human serum albumin (open
bar); Figure 2B further demonstrates neutralization of C.
difficile Toxin B (ToxB) and rescue of viability of cells
by increasing concentrations of virtually pure IgM only
(in micromole/L or uM; solid black bar).
Figure 3 shows the neutralization of C. difficile toxin-
induced Caco-2 permeability. Caco-2 cells were
differentiated by typical methods in Transwell multiwell
plate inserts. After 21 days of differentiation,
Transepithelial electrical resistance (TEER) was measured
immediately before treatments initiated. Only those wells
having a TEER measurement above 200 were included in the
experiment. After 16 hour treatments, TEER was measured to
determine effects of treatments on TEER. Controls (non-
treated cells) were set to 100% as the comparator.
Treatment groups are shown as relative percentages
compared to the control group TEER. For Lucifer Yellow
Permeability experiments, the cells with TEERs above 200
and treated as described in the figure were incubated with
Lucifer Yellow (Life Technologies, Grand Island, NY USA)
solution for 1 hour at 37°C. The Apical and Basal
compartments of the Transwell inserts were sampled and
assessed for the presence of Lucifer Yellow. The
percentage of Lucifer Yellow which passed through the
Caco-2 monolayer was determined by fluorescence
measurement of the samples. Data forpercentage of Lucifer
Yellow passing the Caco-2 monolayer are presented as fold
increase in permeability relative to Controls which were
set to a value of 1. A dose-response is demonstrated to C.
difficile toxin B (Tox B)-mediated cell permeability to
the dye, Lucifer Yellow (A) or to electrical resistance of
the epithelial layers (TEER, vide supra) (B); in both
cases, a non-toxin B control is included (left on graph).
The positive neutralizing effect of co-administration of
IgM with Toxin B (Tox B) is demonstrated in the Lucifer
Yellow permeability study. For the representative
permeability in (C), a control sample (no protein, far
left bar) shows the permeability of Lucifer Yellow alone,
while the remaining bars show the increased permeability
by C. difficile Toxin B (Tox B), with or without added
human serum albumin (HSA), but a neutralizing effect of
Toxin B (Tox B) in the presence of IgM (Frac C), second
bar from right). For the representative transepithelial
electrical resistance measurements (TEER) in (D), a
control sample without protein (solid bar, far left)
demonstrates the normal electrical resistance of the cell
layer, which is considerably reduced in the presence of C.
difficile Toxin B (Tox B) both without (solid bar, second
from left), and with human serum albumin (HSA; solid bar,
far right). Restoration of TEER by IgM (Frac. C) in the
presence of Toxin B (ToxB) is shown in this figure (Tox B
+ Frac C; second from right).
Figures 4A and 4B show the neutralization of Pseudomonas
aeruginosa Exotoxin A cytotoxicity. Caco-2 cells (obtained
from ATCC) were cultured in the recommended proliferation
media. Cells were seeded in 96-well plates at 4000 cells
per well. 24 hours after initial plating, cells were
treated with various IgM preparations and/or Pseudomonas
aeruginosa Exotoxin A as described in the figure legend.
Data for the relative number of cells are shown as RLU, as
measured by the Cell Titer Glow (Promega Corp. Madison,
WI, USA) assay according to the manufacturer’s
instructions. Figure 4A demonstrates specificity of
neutralization of Pseudomonas Exotoxin A (ExA) by a two
different batches of an IgG and IgM mixture (Frac Conc.
45% and 70-80% IgM for solid black bars and hatched bars,
respectively, but not for the non-specific control, human
serum albumin (open bar); Figure 4B further demonstrates
neutralization of Pseudomonas Exotoxin A (P.A. ExA) and
rescue of viability of cells by increasing concentrations
of virtually pure IgM only (in micromole/L or uM; solid
black bars).
Figure 5 shows the neutralization of Clostridium tetani
toxoid effects. Human peripheral blood mononuclear cells
were cultured in RPMI with 10% heat inactivated human
serum. For proliferation assays, 3x10 cells were seeded
in each well of a 96 well plate using culture media. Cells
were treated as described in the figure legend. Relative
cell proliferation was determined by Cell Titer Glow
(Promega Corp. Madison, WI, USA) and performed according
to manufacturer’s instructions. Cell proliferation was
standardized against experimental controls to a value of
Figure 6 shows the immunoreactivity of IgM against
Pseudomonas aeruginosa, Streptococcus pneumoniae, and
Klebsiella pneumoniae bacteria. Absorbance OD readings at
450nm are shown for representative whole cell ELISAs.
Target antigens were formaldehyde treated Pseudomonas
aeruginosa (white bars), Streptococcus pneumoniae
(diagonal striped bars), and Klebsiella pneumoniae (black
bars), whole bacteria cells were coated on ELISA plates.
Controls: bacteria coated wells incubated with secondary
antibody only or wells that have not been coated with
antigen.
DETAILED DESCRIPTION OF THE INVENTION
An embodiment of the present invention provides a method
for treating an infectious disease in a subject, said
method comprising administering a composition to said
subject, said composition comprising, consisting
essentially of, or consisting of plasma-derived IgM and
optionally one or more excipients in a pharmaceutical
carrier, wherein the composition is administered in an
amount effective to neutralize microbial protein products
in said patient.
Another embodiment of the present invention provides a
method for neutralizing microbial protein products in a
subject, said method comprising administering a
composition to said subject, said composition comprising,
consisting essentially of, or consisting of plasma-derived
IgM and optionally one or more excipients in a
pharmaceutical carrier, wherein the composition is
administered in an amount effective to neutralize said
microbial protein products.
Another embodiment of the present invention provides a
composition comprising, consisting essentially of, or
consisting of plasma-derived IgM and optionally one or
more excipients in a pharmaceutical carrier. According to
particular embodiments, the one or more excipients and/or
the pharmaceutical carrier are synthetic, i.e., non-
naturally occurring.
As used herein, “neutralizing” microbial protein products
refers to reducing, preventing or eliminating the toxic
effects of microbial protein products on the subject,
e.g., reducing, preventing or eliminating exotoxin-
mediated toxicity towards a patient.
According to particular embodiments, the microbial protein
products are selected from the group consisting of
exotoxins, superantigens and secreted enzymes. Preferably,
the microbial protein products do not include microbial
endotoxins.
According to particular embodiments, the subject has been
diagnosed with a bacterial infection prior to
administration of the composition.
As used herein, the term “pharmaceutically acceptable
carrier” refers to a diluent, adjuvant, excipient, or
vehicle with which plasma-derived IgM of the present
invention is administered. Such carriers can be sterile
liquids, such as water and oils, including those of
petroleum, animal, vegetable or synthetic origin, such as
peanut oil, soybean oil, mineral oil, sesame oil and the
like, polyethylene glycols, glycerin, propylene glycol or
other synthetic solvents. Saline solutions and aqueous
dextrose and glycerol solutions can also be employed as
liquid carriers, particularly for injectable solutions.
According to particular embodiments, the pharmaceutically
acceptable carrier is synthetic (i.e., the carrier is not
naturally-occurring).
Non-limiting examples of suitable excipients include
starch, glucose, lactose, sucrose, gelatin, silica gel,
sodium stearate, glycerol monostearate, talc, sodium
chloride, glycerol, propylene glycol, water, ethanol and
the like. Excipients may also include wetting or
emulsifying agents, or pH buffering agents such as
acetates, citrates or phosphates; antibacterial agents
such as benzyl alcohol or methyl parabens; antioxidants
such as ascorbic acid or sodium bisulfite; chelating
agents such as ethylenediaminetetraacetic acid; and agents
for the adjustment of tonicity such as sodium chloride or
dextrose. According to particular embodiments, the one or
more excipients are synthetic (i.e., the excipients are
not naturally-occurring).
The cytotoxic exotoxins can be secreted by several
microorganisms such as Escherichia coli, Pseudomonas
aeruginosa, Staphyloccuc aureus, Klebsiella pneumoniae,
Streptococcus pneumoniae, Clostridium difficile,
Clostridium botulinum, Aspergillus flavus and combinations
thereof.
Preferably, the composition containing plasma-derived IgM
is obtained from a waste stream of a standard
fractionation process. The plasma-derived IgM has a purity
of at least 70% (w/v), more preferably at least 90% (w/v),
and the most preferably at least 95% (w/v) .
Also preferably, the dose of plasma-derived IgM to be
administered ranges from 75 mg to 1g per kilogram of the
patient, preferably from 75 mg/kg to 600 mg/kg, more
preferably from 75 mg/kg to 300 mg/kg. The dose can be
administered on a daily, every other day, 3x/week or once
per week, regimen.
Optionally, the composition of plasma-derived IgM further
comprises other molecules such as small molecule
antibiotics, natural or synthetic peptide antimicrobials,
or proteins with antimicrobial properties, or a
combination thereof.
Examples of small molecule antibiotics are vancomycin and
meropenem. An example of proteins with antimicrobial
properties is lactoferrin.
In the method of the present invention, the composition of
plasma-derived IgM can be used alone or in combination
with other therapeutics molecules selected from the group
consisting of therapeutic molecules, including anti-
inflammatory agents, and immunomodulators.
The embodiments described herein are intended to be
exemplary of the invention and not limitations thereof.
One skilled in the art will appreciate that modifications
to the embodiments and examples of the present disclosure
may be made without departing from the scope of the
present disclosure.
The embodiments of the invention are described above using
the term “comprising” and variations thereof. However, it
is the intent of the inventors that the term “comprising”
may be substituted in any of the embodiments described
herein with “consisting of” and “consisting essentially
of” without departing from the scope of the invention.
Unless specified otherwise, all values provided herein
include up to and including the starting points and end
points given.
The following examples further illustrate embodiments of
the invention and are to be construed as illustrative and
not in limitation thereof.
EXAMPLES
Example 1. Immunoreactivity of IgM with exotoxins,
secreted bacterial enzymes and superantigens.
Several ELISAs were developed by the present inventors to
assess immunoreactivity towards a variety target antigens
produced by the bacteria P. aeruginosa, Staphilococcus
aureus, C. tetani, and C. difficile (see Table 1).
Surprisingly, all proteinacious exotoxins and enzymes were
recognized by plasma-derived IgM. A positive reactivity
for all protein-based antigens assessed from these
pathogens was observed. An example ELISA showing
reactivity of IgM in a purified preparation and in plasma
is shown in Figure 1.
Table 1. Summary of antigenic targets that have been
assessed by ELISA. The symbol “+” indicates positive
reactivity. E. coli LPS was used as a positive control, as
it is well characterized that IgM has reactivity against
Gram-negative endotoxins.
Species/Antigen IgM Reactivity
P. aeruginosa Exotoxin A
S. aureus TSST-1 +
S. aureus Staphylokinase +
C. difficile Toxoid A +
C. difficile Toxoid B +
C. difficile Toxin A +
C. difficile Toxin B +
C. tetani Tetanus Toxoid +
E. coli 0111:B4 LPS +
Example 2. Neutralization of cytotoxic effects of C.
difficile Toxin B
A preliminary goal of the present invention was to provide
proof-of-concept for IgM neutralizing exotoxins. Since C.
difficile is an intestinal infection, it was chosen to
utilize a physiologically relevant cell line for studies.
Caco-2 cells are an epithelial colorectal cell line
routinely used for intestinal permeability studies. Caco-2
to be used in cytotoxicity assays was developed.
Incubation time and C. difficile Toxin B concentrations
were optimized (data not shown). Incubation of Toxin B for
24 hours did not show any toxicity and as incubation time
increased the cytotoxicity also increased. Additionally,
we determined that 25 ng/mL gave the highest assay window
of toxicity at 48 hours and showed a plateau at this
point. Concluding assay conditions were set at 15 ng/mL
Toxin B with 48 hours incubation with proliferating cells.
Using these conditions neutralization of toxin with
purification fractions enriched for IgM was assessed and
compared, as well as purified IgM (Figure 2). Fraction A
contains 40-50% IgM and Fraction B contains 70-80% IgM.
HSA had no effect on Toxin B toxicity, whereas 2 different
fractions containing IgM neutralized the toxin (Figure
2A). Purified IgM ( ≥95% IgM) was also shown to be
efficacious in neutralizing C. difficile Toxin B (Figure
2B). There are clearly neutralizing antibodies toward C.
difficile in Fraction A, Fraction B, and purified IgM.
Example 3. Neutralization of C. difficile Toxin B-induced
permeability.
As mentioned in the previous example Caco-2 cells are a
well characterized model of intestinal epithelia transport
and permeability. One of the known consequences of C.
difficile toxins are intestinal permeability. To test
whether purification fractions containing IgM could
neutralize this toxin effect, Caco-2 for use as an
intestinal permeability model was developed. In this
model, Caco-2 cells are differentiated in a monolayer on a
well insert with a permeable membrane for 21 days.
Following differentiation, permeability can be monitored
by measuring the ability of fluorescent small molecules
(Lucifer Yellow in this case) to pass through the cell
monolayer and by using the TEER method (TransEpithelial
Electrical Resistance) to measure the electrical
resistance imparted by the monolayer. When the cells have
increased permeability, the amount of Lucifer Yellow found
on the basolateral side of the membrane is also increased.
In terms of electrical resistance, cells with higher
permeability have lower resistance. To show that these
differences can be measured, a dose response of C.
difficile Toxin B (Figures 3A and 3B) was performed. Both
the ability of Lucifer Yellow to across the monolayer and
the electrical resistance of the monolayer had appropriate
corresponding changes in response to increasing doses of
Toxin B. The ability of Fraction C (enriched to 90-95%
IgM) to neutralize the Toxin B – mediated permeability was
tested. Fraction C and Toxin B were pre-incubated for 1hr
to allow IgM to bind to toxin. Following pre-incubation,
cells were treated with the Fraction C and Toxin B mixture
for 16 hours. After this 16 hour period cells were
assessed for permeability by Lucifer Yellow diffusion
across the monolayer (Figure 3C) and for monolayer TEER
(Figure 3D). For both assay methods, Fraction C provided
protection against the Toxin B, whereas HSA had no effect
on Toxin B. Lucifer Yellow had a complete reversal while
resistance showed only a partial rescue. This is perhaps
due to TEER being more sensitive than Lucifer Yellow assay
method.
Example 4. Neutralization of cytotoxic effects of
Pseudomonas aeruginosa Exotoxin A
Given the positive data from Caco-2 cells with
neutralization of C. difficile Toxin B, a similar assay in
Caco-2 was developed to test Pseudomonas aeruginosa
Exotoxin A. When Fraction A or Fraction B were assessed in
this model, neutralization of Exotoxin A was observed
(Figure 4A). Interestingly, the opposite results were
found with Exotoxin A with respect to the efficaciousness
of the fractions, compared to C. difficile Toxin B; the
Fraction A was more potent than Fraction B for
neutralization of Exotoxin A. Additionally, we also
observed neutralization of Pseudomonas aeruginosa Exotoxin
A cytotoxicity using purified IgM (Figure 4B).
Example 5. Neutralization of Clostridium tetani toxoid
Tetanus toxin is a highly potent neurotoxin that blocks
the release of GABA. Most individuals in the United States
are vaccinated for tetanus. As a model of tetanus toxin
neutralization, a non-toxic toxoid form of tetanus toxin
was utilized to assess whether purified IgM can neutralize
this protein. It was shown antigenic binding of IgM to the
tetanus toxoid (see Table 1). As the toxoid shows no GABA
release blockage, IgM’s neutralization effect was assessed
by proliferation of peripheral blood mononuclear cells
(PBMCs). It is known that stimulation of TCR antigens can
induce proliferation of T-cells and tetanus is a described
stimulant for this proliferation. Therefore, tetanus
toxoid induced PBMC proliferation was tested, in the
presence and absence of IgM (Figure 5). A 3-fold increase
in cell number in the presence of tetanus toxoid alone was
observed, whereas co-treatment with IgM almost completely
blocked this effect at 2.5 µM and showed complete
inhibition at 5 µM.
Example 6. IgM has antigenic recognition of diverse
microbes
To better understand the diversity of various targets a
variety of ELISAs were performed. A variety of
commercially available ELISA kits were used detecting
reactivity with both bacterial and viral pathogens.
Additionally, an ELISA-based assays was utilized in which
whole heat killed or formaldehyde treated microbes were
coated on ELISA plates. This assessment allows assessment
of reactivity against “global” antigen targets produced by
microbes. Data for all ELISAs and Whole Cell ELISAs are
summarized in Table 2 and from these data it can be
concluded that IgM has ubiquitous antigenic recognition.
An example ELISA data set for IgM reactivity in whole cell
ELISAs using Pseudomonas aeruginosa, Streptococcus
pneumoniae, and Klebsiella pneumoniae bacteria are shown
in Figure 6.
Table 2 – Summary of antigenic targets that have been
assessed by ELISA and Whole Cell ELISA. The symbol “+”
indicates positive IgM reactivity and “+ weak” indicates
weak IgM reactivity based on the kit standard controls.
Viral ELISAs Species IgM Reactivity
Adenovirus + weak
Cytomegalovirus + weak
Measles + weak
Mumps +
Rubella +
Respiratory Syncytial Virus +
Varicella-Zoster +
Rotavirus +
Bacterial Whole Cell ELISAs Species IgM Reactivity
E.coli 0111:B4 +
Helicobacter pylori +
Listeria monocytogenes +
Legionella pneumophila +
Lactobacillus rhamnosus +
Pseudomonas aeruginosa +
Porphyromonas gingivalis +
Staphylococcus aureus +
Staphylococcus aureus (Prot. A def.) +
Streptococcus pneumoniae +
Clostridium difficile +
Klebsiella pneumoniae ATCC 10031 +
Klebsiella pneumoniae UNT1 +
Pseudomonas aeruginosa UNT1 +
Streptococcus pneumoniae UNT1 +
Fungal Whole Cell ELISAs Species IgM Reactivity
Candida albicans +
Claims (25)
1. A method for neutralizing secreted cytotoxic exotoxins during active microbial infections comprising 5 administering a composition to said subject, said composition comprising plasma-derived IgM and optionally one or more excipients in a pharmaceutical carrier, wherein the composition is administered in an amount effective to neutralize said secreted cytotoxic exotoxins.
2. The method according to claim 1, wherein said composition containing plasma-derived IgM is obtained from a waste stream of a standard blood fractionation process. 15
3. The method according to claim 1, wherein the plasma- derived IgM has a purity of at least 70% (w/v).
4. The method according to claim 1, wherein the plasma- derived IgM has a purity of at least 90% (w/v).
5. The method according to claim 1, wherein the plasma- derived IgM has a purity of at least 95% (w/v).
6. The method according to claim 1, wherein the dose of 25 plasma-derived IgM to be administered to the patient ranges from 75 mg to 1g per kilogram of the patient.
7. The method according to claim 1, wherein the dose of plasma-derived IgM to be administered to the patient 30 ranges from 75 mg to 600 mg per kilogram of the patient.
8. The method according to claim 1, wherein the dose of plasma-derived IgM to be administered to the patient ranges from 75 mg to 300 mg per kilogram of the patient. 5
9. The method according to claim 1, wherein the dose can be administered on a daily, or every other day, or 3x/week or once per week, regimen.
10. The method according to claim 1, wherein the 10 composition of plasma-derived IgM further comprises other molecules selected from small molecule antibiotics, natural or synthetic peptide antimicrobials, or proteins with antimicrobial properties, or a combination thereof. 15
11. The method according to claim 10, wherein said small molecule antibiotic is vancomycin or meropenem.
12. The method according to claim 10, wherein said protein with antimicrobial properties is lactoferrin.
13. A method for treating an infectious disease in a subject comprising administering a composition to said subject, said composition comprising plasma-derived IgM and optionally one or more excipients in a pharmaceutical 25 carrier, wherein said composition is administered in an amount effective to neutralize microbial protein products in said patient.
14. A composition comprising plasma-derived IgM and 30 optionally one or more excipients in a pharmaceutical carrier for the treatment of a condition related with secreted cytotoxic exotoxins during active microbial infections.
15. The composition according to claim 14, wherein said plasma-derived IgM is obtained from a waste stream of a standard blood fractionation process. 5
16. The composition according to claim 14, wherein the plasma-derived IgM has a purity of at least 70% (w/v).
17. The composition according to claim 14, wherein the plasma-derived IgM has a purity of at least 90% (w/v).
18. The composition according to claim 14, wherein the plasma-derived IgM has a purity of at least 95% (w/v).
19. The composition according to claim 14, wherein the 15 dose of plasma-derived IgM to be administered to the patient ranges from 75 mg to 1g per kilogram of the patient.
20. The composition according to claim 14, wherein the 20 dose of plasma-derived IgM to be administered to the patient ranges from 75 mg to 600 mg per kilogram of the patient.
21. The composition according to claim 14, wherein the 25 dose of plasma-derived IgM to be administered to the patient ranges from 75 mg to 300 mg per kilogram of the patient.
22. The composition according to claim 14, wherein the 30 dose can be administered on a daily, or every other day, or 3x/week or once per week, regimen.
23. The composition according to claim 14, wherein said composition further comprises other molecules such as small molecule antibiotics, natural or synthetic peptide antimicrobials, or proteins with antimicrobial properties, 5 or a combination thereof.
24. The composition according to claim 23, wherein said small molecule antibiotic is vancomycin or meropenem. 10
25. The composition according to claim 23, wherein said protein with antimicrobial properties is lactoferrin.
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US62/201,910 | 2015-08-06 |
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