U.S. patent application number 16/918494 was filed with the patent office on 2020-12-24 for devices and methods for on-line whole blood treatment.
The applicant listed for this patent is Qualigen Inc.. Invention is credited to Michael Poirier.
Application Number | 20200397985 16/918494 |
Document ID | / |
Family ID | 1000005062478 |
Filed Date | 2020-12-24 |
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United States Patent
Application |
20200397985 |
Kind Code |
A1 |
Poirier; Michael |
December 24, 2020 |
DEVICES AND METHODS FOR ON-LINE WHOLE BLOOD TREATMENT
Abstract
A whole blood treatment device includes a first conduit, a
second conduit, and a rotating or reciprocating element having a
channel. The first and second conduits are fluidly coupled to the
rotating or reciprocating element such that the channel is fluidly
continuous with the first conduit when the channel is fluidly
discontinuous with the second conduit, and such that the channel is
fluidly discontinuous with the first conduit when the channel is
fluidly continuous with the second conduit. The first conduit is
configured to receive whole blood, and the second conduit is
configured to receive a regeneration fluid. The channel comprises a
surface that is modified with an affinity agent at a concentration
effective to allow removal of a target compound from whole
blood.
Inventors: |
Poirier; Michael; (Vista,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Qualigen Inc. |
Carlsbad |
CA |
US |
|
|
Family ID: |
1000005062478 |
Appl. No.: |
16/918494 |
Filed: |
July 1, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15913729 |
Mar 6, 2018 |
10744258 |
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16918494 |
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62467408 |
Mar 6, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M 2202/206 20130101;
A61M 27/002 20130101; B01D 2215/022 20130101; B01D 15/1892
20130101; B01D 15/3809 20130101; A61M 2202/049 20130101; B01D
15/203 20130101; A61M 2202/0447 20130101; A61M 5/165 20130101; A61M
2205/3344 20130101; A61M 2205/106 20130101; A61M 2209/088 20130101;
A61M 2205/103 20130101; A61M 2206/14 20130101; B01D 15/3823
20130101; A61M 2202/203 20130101 |
International
Class: |
A61M 5/165 20060101
A61M005/165; B01D 15/38 20060101 B01D015/38; B01D 15/18 20060101
B01D015/18; B01D 15/20 20060101 B01D015/20; A61M 27/00 20060101
A61M027/00 |
Claims
1-13. (canceled)
14. A method of removing a target compound from whole blood of a
mammal in a whole blood treatment device, comprising: (a) moving
the whole blood through a channel in a rotating or reciprocating
element while the channel is fluidly coupled to a first conduit
that contains the whole blood; wherein the channel comprises a
surface that is modified with an affinity agent at a concentration
effective to allow removal of a target compound from whole blood;
(b) moving the rotating or reciprocating element in a position such
that the channel is fluidly disconnected from the first conduit and
fluidly connected with a second conduit; (c) eluting the target
compound from the surface while the channel is fluidly connected
with the second conduit; and (d) further moving the rotating or
reciprocating element in a position such that the channel is
fluidly connected with the first conduit and fluidly disconnected
with the second conduit, wherein the rotating or reciprocating
element is selected from the group consisting of a wheel, an
Archimedean screw and a reciprocating piston.
15-17. (canceled)
18. The method of claim 14 wherein the rotating or reciprocating
element further comprises a third conduit that is fluidly coupled
to an analyzer, and further comprising a step of using the analyzer
to measure a quantity of an analyte in the whole blood or
eluate.
19. The method of claim 14 wherein the rotating or reciprocating
element further comprises a fourth conduit that is fluidly coupled
to a dispensing device, and further comprising a step of using the
dispensing device to dispense a measured quantity of a
pharmaceutical agent into the whole blood.
20. The method of claim 14 wherein the steps (a)-(d) are performed
while the mammal wears the device on the body.
21-22. (canceled)
23. A method of palliative treatment of a patient, comprising:
ascertaining that at least one of an IL-8 level and a CRP level is
elevated above normal as a consequence of a disorder or
pharmaceutical intervention; and continuously reducing at least one
of IL-8 and CRP in whole blood of the patient using the device of
claim 1 that is configured to bind at least one of IL-8 and
CRP.
24. The method of claim 23 wherein the IL-8 level and the CRP level
are elevated.
25. The method of claim 23 wherein the at least one of the IL-8
level and the CRP are elevated as a consequence of pharmaceutical
intervention.
26. The method of claim 25 wherein the pharmaceutical intervention
is a chemotherapy for treatment of a neoplastic disease.
27. The method of claim 23 wherein the disorder is a chronic
inflammatory disease.
28. The method of claim 23 wherein the at least one of the IL-8 and
the CRP are reduced to normal reference level.
29-41. (canceled)
42. The method of claim 14, wherein the affinity agent is selected
from the group consisting of antibodies, aptamers and small
molecules.
43. The method of claim 14, wherein the target compound is
IL-8.
44. The method of claim 43, wherein the affinity agent is selected
from the group consisting of: HuMab 10F8, glycosaminoglycan (GAG)
heparin, protease inhibitor alpha2-macroglobulin and Cyclosporin
A.
45. (canceled)
46. The method of claim 14, wherein the target compound is CRP.
47. (canceled)
48. The method of claim 14, wherein the target compound is selected
from the group consisting of: cellular components, extracellular
components, and cells.
49. The method of claim 14, wherein the target compound is an
inhibitory checkpoint molecule.
50. The method of claim 14, wherein the target compound is an
inflammatory factor.
51. The method of claim 14, wherein the target compound is
cancerous cells.
52. The method of claim 51, wherein the affinity agent is an
anti-nucleolin antibody.
53. The method of claim 14, wherein the target compound is selected
from the group consisting of: viruses, bacteria and toxins.
54. (canceled)
55. (canceled)
Description
FIELD OF THE INVENTION
[0001] The field of the invention is treatment of whole blood,
especially as it relates to in vivo continuous removal of one or
more components contained in whole blood.
BACKGROUND
[0002] Removal of various undesirable components from whole blood
is well known and often includes ex vivo separation of cellular
components (e.g., centrifugation or filtration) to obtain a
cell-free fluid that is then processed, typically using affinity
media and/or enzymatic treatment. While such treatment is standard
practice in many instances, hemolysis is often a problem. Still
more disadvantageously, such known treatment typically requires
relatively large equipment and is therefore impractical in
ambulatory use.
[0003] Further known methods for binding of a contaminant from a
fluid are described in WO 2011/005742 where a sorbent medium is
modified and combined with the fluid. However, the sorbent medium
must be separated from cellular components, which is in most cases
not feasible to the required degree. To assist in separation of the
sorbent, magnetic beads can be used as is described in U.S. Pat.
No. 6,143,510. However, such methods are generally limited to ex
vivo tests as residual quantities of magnetic beads are highly
undesirable. To circumvent problems associated with removal of
sorbent, selective permeable membranes may be employed as taught in
US 2009/0114595. While such removal is conceptually simple,
separation efficiency is in at least some cases less than
desirable, especially where large molecules are separated. Thus,
there is still a need to provide improved whole blood separation
devices and methods.
SUMMARY OF THE INVENTION
[0004] The present inventive subject matter is directed to
diagnostic and therapeutic devices in which whole blood is passed
through one or more channels of a rotating or reciprocating element
wherein the channels comprise an affinity agent to allow specific
binding of a target compound to the channel. Due to the rotating or
reciprocating motion of the element, the channel can be moved into
and out of fluid communication with the circulatory system of a
mammal such that the affinity agent binds the target compound when
the channel is in fluid communication with the circulatory system
and such that bound target antigen can be removed from the affinity
agent when the channel is removed from the fluid communication with
the circulatory system and in fluid communication with a
regeneration circuit.
[0005] In one aspect of the inventive subject matter, the rotating
or reciprocating element has multiple channels and is configured as
a rotating wheel, and multiple conduits are separately provided to
the channels in the wheel to allow concurrent adsorption of the
target compound to one channel while regenerating the affinity
agent in another channel. Alternatively, the element may also be
configured as an Archimedean screw or a reciprocating piston.
Consequently, it should be recognized a target compound can be
continuously removed from the blood stream on-line and in vivo as
such devices and methods allow for multiple passes of whole blood
through the device without saturating the affinity agent.
[0006] Various objects, features, aspects and advantages of the
present invention will become more apparent from the following
detailed description of preferred embodiments of the invention.
[0007] Most typically, contemplated devices will therefore include
a first conduit, a second conduit, and a rotating or reciprocating
element having a channel, wherein the first and second conduits are
fluidly coupled to the rotating or reciprocating element such that
the channel is fluidly continuous with the first conduit when the
channel is fluidly discontinuous with the second conduit, and such
that the channel is fluidly discontinuous with the first conduit
when the channel is fluidly continuous with the second conduit. The
first conduit is preferably configured to receive whole blood
(directly from the circulation in an on-line mode, or indirectly,
via blood collection bag or other implement), and the second
conduit is preferably configured to receive a regeneration fluid
(typically from a reservoir or device that prepares the
regeneration fluid in situ). Regardless of the particular
configuration, the channel will have a surface that is modified
with an affinity agent (most typically an antibody or antibody
fragment, a nucleic acid or nucleic acid analog, a lectin, etc.) at
a concentration effective to allow removal of a target compound
from whole blood, wherein the target compound is capable of binding
with high specificity and affinity to the affinity agent.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1A illustrates a whole blood treatment device including
a wheel.
[0009] FIG. 1B illustrates a whole blood treatment device including
an Archimedean screw.
[0010] FIG. 1C illustrates a whole blood treatment device including
a reciprocating piston.
DETAILED DESCRIPTION
[0011] FIG. 1A depicts an exemplary device in which the rotating or
reciprocating element is configured as a wheel having a plurality
of conduits extending through the wheel. The wheel is preferably
rotatably coupled to at least two conduits, which are here
indicated as half-pipes with abutting surfaces to so form a
cylindrical structure. In the example of FIG. 1A, the wheel is
disposed in the middle of the conduits such that flow of whole
blood enters the upper conduit at the site marked `whole blood
inlet`, passes through the upper three channels that are coated
with an antibody (e.g., specific against IL-8), and continues to
flow through the upper half-pipe to exit at the site marked `whole
blood outlet`. During this pass, target compounds will bind to the
affinity agents. Similarly, and preferably at the same time, flow
of regeneration fluid enters the lower conduit at the site marked
`regen fluid inlet`, passes through the lower three channels and
causes the bound target compounds to elute into the regeneration
fluid, which flows through and exits the lower half-pipe to leave
the pipe at the site marked `regen fluid outlet`.
[0012] It should be appreciated that the wheel will rotate during
operation, preferably at a speed that will allow saturation of the
affinity agents with the target compound during the presence of the
channel in the upper half-pipe. Once saturated, and due to the
preferably continuous rotation of the wheel, the channel with the
saturated affinity agents will enter the lower half-pipe and is
then exposed to the regeneration fluid for regeneration of the
affinity agent. Once regenerated, and due to the preferably
continuous rotation of the wheel, the channel with the regenerated
affinity agents will enter the lower half-pipe and is once again
available for a new cycle of binding and regeneration.
[0013] Alternatively, and as depicted in FIG. 1B, the rotating or
reciprocating element is configured as a Archimedean screw that
fittingly extends through the length of a cylindrical main pipe. At
about the middle of the pipe, two fluid conduits join the main pipe
in a manner such that (a) fluid entering on one branch of the main
pipe is pumped along the pipe and exits one of the two joining
conduits, and (b) fluid entering the other of the two joining
conduits is pumped into and along the other branch and exits the
other branch. In this example, the channel is formed by the helical
groove of the screw and is also coated with (or otherwise coupled
to) an affinity agent. Thus, in the example of FIG. 1B, whole blood
flows through one branch of the main pipe for adsorption of the
target compound, while at the same time regeneration fluid flows
through the other main branch for regeneration of the affinity
agent. Flow of the whole blood and the regeneration fluid is then
alternatingly controlled such that when the affinity agents are
saturated in one branch, whole blood flow is routed to the other
branch that is now regenerated. Regeneration fluid is then routed
to the saturated channel to regenerate the binding surface. Viewed
from a different perspective, the operational mode between binding
and regeneration is switched by switching flow though the
device.
[0014] Alternatively, the moving element may also be configured as
a reciprocating piston with one or more channels extending through
the piston as exemplarily illustrated in FIG. 1C. Here, the piston
has a plurality of channels where two channels are concurrently
employed for binding and absorption. In this example, the
regenerated channel is moved into the flow of whole blood as the
binding channel is saturated. FIG. 1C shows an additional channel
which may be employed for measurement of an analyte and/or
dispensation of a pharmaceutical agent. Once more, it should be
appreciated that binding and regeneration can be performed
continuously and that such systems are particularly useful for
continuous on-line separation of a target compound from whole
blood.
[0015] Consequently, it should be recognized that method of
removing a target compound from whole blood of a mammal is
contemplated. More specifically, contemplated methods include a
step of moving the whole blood through a channel in a rotating or
reciprocating element while the channel is fluidly coupled to a
first conduit that contains the whole blood, wherein the channel
comprises a surface that is modified with an affinity agent at a
concentration effective to allow removal of a target compound from
whole blood. In another step, the rotating or reciprocating element
is moved into a position such that the channel is fluidly
disconnected from the first conduit and fluidly connected with a
second conduit, and in yet another step, the target compound is
eluted from the surface while the channel is fluidly connected with
the second conduit. The rotating or reciprocating element is then
further moved into a position such that the channel is fluidly
connected with the first conduit and fluidly disconnected with the
second conduit.
[0016] While it is in most aspects preferred that the affinity
agent in contemplated devices and methods is continuously or
intermittently regenerated, it should also be appreciated that the
affinity agent may be saturated and then discarded (e.g., via user
replacement of the rotating or reciprocating element, or via
replacement of the channel where the channel is configured as a
cylinder). Consequently, another embodiment of a whole blood
treatment device may include a first conduit, a sealing area, and a
rotating or reciprocating element having a channel, wherein the
first conduit is fluidly coupled to the rotating or reciprocating
element such that the channel is fluidly continuous with the first
conduit when the channel is fluidly discontinuous with the sealing
area, and such that the channel is fluidly discontinuous with the
first conduit when the channel is fluidly continuous with the
sealing area. In such devices, the first conduit is configured to
receive whole blood, and the sealing area is configured to allow
flow-less incubation of the whole blood in the channel when the
channel is fluidly continuous with the sealing area. Thus, and
viewed from a different perspective, a volume of whole blood is
captured in the channel while the channel is in contact with the
sealing area to so allow binding of a target compound from an
essentially non-moving or non-flowing volume of whole blood. Such
incubation is considered to improve binding efficiency, especially
where the volume-to-surface ratio is relatively high. As noted
before, the channel will include a surface that is modified with an
affinity agent at a concentration effective to allow removal of a
target compound from whole blood. Where desirable, the rotating or
reciprocating element is disposable and/or user-replaceable, and/or
the channel is configured as a replaceable cylinder.
[0017] Typical non-regenerating devices are similar to the devices
shown in FIG. 1A-1C, however, will not provide second conduits for
regeneration fluid. For example, the second conduit in the device
of FIG. 1 is entirely omitted and a sealing plate or other sealing
implement will seal off the lower conduit. Similarly, the
Archimedean screw configuration of FIG. 1B is simplified in that
the perpendicular in- and outlet ports can be omitted. In such
case, it is generally preferred that two linear conduits will have
two independent Archimedean screws with one screw operating while
the other screw is not operating and replaceable. Increased
incubation time is then achieved by discontinuous rotation, or by
addition of a second (third, or higher) screw that operates in a
parallel and alternating mode. In the device of FIG. 1C, the device
configuration is again simplified by providing one or more flow
channels through the reciprocating block. Reciprocating movement of
the block will then position a volume of whole blood in a channel
between sealing surfaces for a predetermined time to allow longer
incubation, and reversal of that movement (or additional forward
movement) will then move the treated volume back into
circulation.
[0018] It is especially preferred that contemplated devices are
configured to be wearable, and that the reciprocating or rotating
element can be readily exchanged, preferably by a non-medical
professional (e.g., end user or caretaker). Thus, in especially
preferred aspects, the device has a housing that encloses at least
partially the element and conduits. Fluid lines from the patient's
circulation and/or regeneration fluid are preferably attachable via
luer lock or other suitable connector that preferably allows
maintaining sterile working conditions. Moreover, where the device
is configured as a user-wearable device, the regeneration fluid
(and other fluids, including wash fluids) are preferably also in a
wearable format, and most preferably flexible pouches.
[0019] In further preferred aspects of the inventive subject
matter, it should be appreciated that the device may include more
than one rotating or reciprocating element and/or that there are
more than one type of affinity agent in one or more channels.
Likewise, it should be recognized that contemplated devices and
methods are not limited to those having only two conduits, but any
number of conduits are deemed suitable. Additional conduits may be
used for measurement of one or more analytes in the whole blood
and/or the regeneration fluid, and/or for provision of wash fluids
and/or pharmaceutical agent. Of course, contemplated device may
also implement additional functionalities using a flow splitter
that may be upstream or downstream, of the wheel (with respect to
the flow of the whole blood). The so produced bypass or slipstream
can then be treated or analyzed as desired, and fed back to the
circulation or be discarded into a typically disposable waste
container.
[0020] While continuous flow of whole blood through the device is
generally preferred, it is also contemplated that intermittent flow
may be directed through the device. In such case, or where a stop
valve is activated in the flow path, the conduit may include or may
be coupled to a surge compartment to accommodate discontinuous flow
and to maintain constant flow rate through the device. Thus,
contemplated devices may have a continuously operating pump, a pump
that operates in on-off mode, or no pump at all. Thus, the whole
blood may be driven by an active pump (e.g., peristaltic, piston,
etc.), or passively by a blood pressure driven mechanism.
Similarly, it is generally preferred that the reciprocating or
rotating element is actuated by a motor or other actuator,
preferably in a continuous manner at constant speed. However, where
desirable, the speed of the rotating or reciprocating element may
also be variable and/or in an intermittent pattern.
[0021] The number and geometry of channel may vary considerably and
will predominantly be determined by the desired flow rate of whole
blood through the element, the quantity of target compound in the
whole blood, and affinity of the target compound. It is generally
preferred that the channels are formed to reduce or even entirely
avoid turbulent flow. Thus, channels are preferably linear or
helical with a larger-than-capillary diameter (e.g., at least 50
micron, more preferably at least 100 micron, and most preferably at
least 250 micron). It is further noted that the transition of a
channel from blood to regeneration fluid may include a rinse step
in the device and/or via a flow loop with one or more valves. Thus,
most preferably, loss of whole blood is avoided as the volume of
whole blood in the channel may be recycled back to the mammal
(e.g., using isotonic fluid as a wash fluid).
[0022] Sealing of the movable element against fluid and blood loss
can be achieved in numerous manners well known in the art. For
example, rotary seals, rubber lip seals, or bore seals with 0-rings
are deemed suitable for use herein. Similarly, press-fit tolerance
may be employed to reduce leakage of the channel/conduit
interface.
[0023] Many various target compounds can be targeted for removal
from the blood, and various affinity agents can be used, where the
affinity agents have a binding affinity to the target compound to
be removed. The inventors have now discovered that chemotherapy
compliance can be significantly improved when IL-8 and/or CRP
concentrations are reduced in whole blood of a patient that is
treated with a drug that increases at least one of IL-8 and/or CRP.
In especially preferred aspects, IL-8/CRP reduction is performed
on-line in a continuous manner using a wearable device, such as the
device described herein. The device can be used to remove other
antigens and small molecules from whole blood by passing the blood
through channels, which comprise an affinity agent to bind to the
target compound.
[0024] In one particularly preferred aspect of the inventive
subject matter, IL-8 and CRP levels are elevated in whole blood of
a patient undergoing taxane (e.g., paclitaxel or decetaxel)
chemotherapy, for example, in the treatment of pancreatic cancer.
Such treatment may be in combination with other drugs, for example,
gemzitabine. Most typically, chemotherapy in such and similar cases
is not well tolerated and a significant fraction of patients will
discontinue treatment due to the severe side effects.
[0025] The inventors have determined that IL-8 and CRP levels in
patients about to discontinue chemotherapy is well above normal
reference ranges, typically at least 25%, and most typically at
least 50% above the upper range of normal, and contemplate that
continuous reduction of the elevated levels, preferably back to
reference range, will increase the level of compliance. It is
generally preferred that the continuous treatment will extend over
a period of at least 12 hours, more typically at least 24 hours,
and most typically over at least 3 days. Thus, and viewed from
another perspective, it is contemplated that the reduction of IL-8
and/or CRP will be effected over a period that coincides with at
least a portion of time over which elevated levels will be observed
without treatment.
[0026] In this context, it should be noted that the reduction of
IL-8 and/or CRP is not intended as a treatment modality of the
underlying disease, but as a palliative treatment of a condition
that is brought about by pharmacological intervention. Thus,
methods presented herein are targeted to improve subjective
well-being of a patient, and especially relieve nausea, flu-like
symptoms, loss of appetite, and physical and/or metal fatigue.
[0027] However, and with respect to the disease being treated, it
should be appreciated that any disease that requires drug
treatment, and/or any disease that is characterized by excessive
blood concentrations of IL-8 and/or CRP is contemplated herein. For
example, contemplated methods may be effective not only in
combating side effects of chemotherapy of various neoplastic
diseases, but also infectious diseases and especially including
viral diseases (and particularly influenza virus, H1N1 flu, SARS,
etc.), chronic inflammatory diseases (e.g., COPD, rheumatoid
arthritis, inflammatory bowel disease, psoriasis, etc.),
atherosclerosis, and acute coronary syndrome.
[0028] Consequently, and depending on the particular nature of
disease or treatment, it should be appreciated that the
chemotherapeutic agent may vary considerably. Most typically,
however, the pharmaceutical treatment will include chemotherapy for
various neoplastic diseases, and especially those agents that are
known to be associated with an increase in IL-8 and/or CRP. For
example, contemplated chemotherapies may include administration of
one or more of receptor antibodies, alkylating agents,
antimetabolites, microtubule inhibitors (and especially taxanes),
topoisomerases, and kinase inhibitors. Similarly, contemplated
methods may be implemented on an intermittent or continuous basis,
and it is generally contemplated that the reduction in IL-8 and/or
CRP is performed as long as excessive levels of IL-8 and/or CRP are
measured or anticipated. For example, where administration of a
chemotherapeutic agent results in a relatively broad and temporary
spike in blood IL-8 levels (e.g., over 2 days), reduction of IL-8
may be performed in a continuous manner over two days. On the other
hand, where the increase is relatively brief, reduction may be
performed in a discontinuous manner immediately following
administration of the chemotherapeutic agent. On the other hand,
where the elevated levels of IL-8 and/or CRP are, for example, due
to a chronic inflammatory condition, continuous reduction in IL-8
and/or CRP may be advisable.
[0029] Removal is preferably monitored to achieve a continuous IL-8
and/or CRP level that is within the normal reference range (and in
some cases below or slightly above). For example, the clinical
range of IL-8 is typically between 10-80 pg/ml for a healthy
person, and it is typically preferred that reduction of IL-8 is to
equal or less than 100 pg/ml, and more preferably to equal or less
than 80 pg/ml. Similarly, the clinical normal range for CRP is
between 0-5 mg/l for male and 0-8 for female healthy adults, and it
is typically preferred that reduction of CRP is to equal or less
than 5 mg/1, more preferably to equal or less than 3 mg/l, and most
preferably to equal or less than 1 mg/l.
[0030] Reduction of IL-8 and/or CRP is preferably effected via
specific antibodies (e.g., HuMab 10F8 for IL-8), or other known
IL-8 binders, including glycosaminoglycan (GAG) heparin, protease
inhibitor alpha2-macroglobulin, Cyclosporin A, however, engineered
binding agents are also deemed suitable, including recombinant IL-8
receptor and fragments thereof. Similarly, it is contemplated that
CRP can be reduced by binding of CRP to one or more types of
monoclonal or polyclonal antibodies, Fc receptors (e.g.,
Fc.gamma.RIIa), etc., and the number of binding agents needed to
reduce the IL-8 and/or CRP levels will preferably be chosen such
that continuous treatment for at least 2, and more typically 4
consecutive days is possible without patient intervention.
[0031] The device may also be used to target other cellular
components and extracellular components, such as proteins, fats and
small molecules, and may also be used to target cells. The whole
blood treatment device can also be used to treat various diseases
that are caused by one or more target compounds. Examples of these
disease include treating cancer by reducing inhibitory checkpoint
molecules or removing cancer cells, autoimmune diseases by reducing
inflammatory factors, cardiovascular disease by reducing
low-density lipoprotein, metabolic diseases such as diabetes by
reducing glucose, viral infection and bacterial infection by
reducing the amount of virus, bacteria or associated toxin, and
toxin exposure and heavy metal exposure by removing the toxin or
heavy metal. Such diseases may be treated with the device by
determining a target compound that can be removed from the body,
and determining an affinity agent that binds to the target
compound. Antibodies or aptamers suited to binding the selected
target compound could be used as the affinity agents, but it is
understood that other compounds could also be used.
[0032] Inhibitory checkpoint molecules are secreted by cancer cells
to reduce the immune response. There are several antibody drugs
(referred to as immune checkpoint inhibitors or immune checkpoint
blockades) that target these inhibitory checkpoint molecules in
order to increase the immune response to cancer cells. Rather than
using these antibodies as a drug, the whole blood treatment devices
pass whole blood through channels with a surface modified with
affinity agents, where the inhibitory checkpoint molecules are
bound by the affinity agents, and removed from the blood, reducing
the concentration of inhibitory checkpoint molecules in the blood.
Some examples of inhibitory checkpoint molecules are cytotoxic
T-lymphocyte associated protein 4 (CTLA-4), programmed cell death-1
(PD-1), programmed death-ligand 1 (PD-L1), B7-1, B7-2, FOXP3.sup.+,
FOXP3.sup.-, Treg 17, Trl, Th3, IL-10, and TGF-.beta.. Some
examples of antibody drugs that could be used as affinity agents
include ipilimumab, ticilimumab, pembrolizumab, atezolizumab and
nivolumab, along with many others, as described in Ghirelli et al.
("Targeting immunosuppression for cancer therapy" J Clin Invest.
2013; 123(6):2355-2357).
[0033] Inflammatory factors are often reduced using antibody drug
treatments. Rather than administering antibodies as drugs, these
same antibodies can be used in the channels of the whole blood
treatment devices to bind inflammatory factors to reduce the
concentration of inflammatory factors in the blood. Inflammatory
factors may include IL-4, IL-10, TNF.alpha., IL-17A, IL-17F, CRP,
TNF, IL-1.alpha., IL-1.beta., IL-5, IL-6, IL-8, IL-12, IL-23, CD2,
CD3, CD20, CD22, CD52, CD80, CD86, C5 complement protein, BAFF,
APRIL, IgE, .alpha.4.beta.1 integrin and .alpha.4.beta.7 integrin.
These inflammatory factors may be bound by IL-17A/F antibodies,
abatacept, alefacept, alemtuzumab, atacicept, belimumab,
canakinumab, eculizumab, epratuzumab, natalizumab, ocrelizumab,
ofatumumab, omalizumab, otelixizumab, rituximab, teplizumab,
vedolizumab, adalimumab, briakinumab, certolizumab pegol,
etanercept, golimumab, infliximab, mepolizumab, reslizumab,
tocilizumab and ustekinumab. Other antibodies or aptamers could
also be used to target inflammatory factors as shown in Focosi et
al. ("Immunosuppressive monoclonal antibodies: current and next
generation" Clin Microbiol Infect 2011; 17: 1759-1768) and Chan, A.
C. et al. ("Therapeutic antibodies for autoimmunity and
inflammation", Nature Reviews Immunology, vol. 10, pp. 301-316,
(2010)). Diseases that could be treated by targeting inflammatory
factors include asthma, rheumatoid arthritis, autoimmune disorders
and gastrointestinal diseases.
[0034] Viruses can be targeted using various drugs. However,
removing these from the blood, via a whole blood treatment device
would reduce unintended side effects. The target compounds can
include viruses and cells infected with viruses. Examples of
viruses include chickenpox, flu (influenza), herpes, human
immunodeficiency virus (HIV/AIDS), human papillomavirus (HPV),
infectious mononucleosis, mumps, measles, rubella and shingles.
Antibodies that bind to these viruses may be used as the affinity
agent, and can be prepared by well-known methods.
[0035] Antibodies can be used to treat various cancers. Rather than
using antibodies that bind cancer cells as a drug, these antibodies
can be used in a channel of a whole blood treatment device.
Examples of cancer cells include skin, breast, lung, pancreas,
kidney, leukemia, lymphoma, and many other types of cancer. For
example, treatment of cancer can be carried out by targeting cells
displaying nucleolin on the cell surface. Anti-nucleolin antibodies
can bind to the nucleolin on the surface of the cancer cell.
Various anti-nucleolin antibodies include p7-1A4 mouse monoclonal
antibody, sc-8031 mouse mAb, sc-9893 goat polyclonal Ab (pAb),
sc-9892 goat pAb, clone 4E2 mouse mAb, and clone 3G4B2 mouse mAb,
which may be used as affinity agents. Other examples of antibody
drugs to treat cancer cells, which may be used as affinity agents
include alemtuzumab, trastuzumab, Ibritumomab tiuxetan, Brentuximab
vedotin, Ado-trastuzumab emtansine, denileukin diftitox, and
blinatumomab, along with other can be found in American Cancer
Society; Monoclonal Antibodies to Treat Cancer (available at
www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immu-
notherapy/monoclonal-antibodies.html). Other drugs may be used to
bind cancer cells within the device.
[0036] Heavy metal poisoning may be treated with a whole blood
treatment device to reduce the concentration of heavy metals to a
safe level. Heavy metals may include lead, mercury, arsenic and
cadmium. These metals can be bound by an affinity agent such as
DNAzyme as described in Zhang et al. ("Metal Ion Sensors Based on
DNAzymes and Related DNA Molecules" Annual review of analytical
chemistry 2011; 4(1):105-128). Chelating agents could also be used
as an affinity agent to bind to the target compounds in the
device.
[0037] Alzheimer's disease can be treated with solanezumab. Rather
than administering this drug to a patient, a whole blood treatment
device can be used to filter target compounds from whole blood,
using the antibody as an affinity agent. Some examples of target
compounds for Alzheimer's disease include misfolded amyloid beta
and tau proteins.
[0038] Bacteria and toxins in the bloodstream can be treated with
various drugs. Rather than administering these drugs to a patient,
a whole blood treatment device can be used to filter the bacteria
or toxins from whole blood. Examples of toxins which could be
target compounds include botulinum toxin produced by Clostridium
botulinum, Corynebacterium diphtheriae toxin, produced during
life-threatening symptoms of diphtheria, and tetanospasmin produced
by Clostridium tetani. Antibodies and aptamers may be used as
affinity agents for the bacteria or toxins. Such antibodies and
aptamers may be prepared by well-known methods.
[0039] Various potent cytokines, including tumor necrosis factor
(TNF) and interleukin 1, are at increased concentrations in the
blood of patients with sepsis. Furthermore, inhibitory checkpoint
molecules are also present in increased concentration in the blood
of patients with sepsis. These are described in Hotchkiss et al.
("Immunosuppression in sepsis: a novel understanding of the
disorder and a new therapeutic approach" The Lancet infectious
diseases. 2013; 13(3):260-268). A whole blood treatment device can
be used to filter the cytokines or inhibitory checkpoint molecules
from whole blood. Antibodies and aptamers may be used as affinity
agents for the bacteria or toxins.
[0040] Methanol poisoning can be treated by competitive inhibition.
Methanol concentration could also be reduced using the whole blood
treatment device with affinity agents such as aptamers.
[0041] Heroin overdoses can be treated by various drugs. Rather
than administering these drugs, a whole blood treatment device
could be used to reduce the concentration of opioids in the blood.
Antibodies, aptamers or other compounds may be used as affinity
agents for the opioids.
[0042] Methods of making antibodies are well-known in the art.
Monoclonal antibodies are usually made by fusing mouse spleen cells
immunized with a desired antigen with myeloma cells (B-cell cancer
cells, which are known for producing antibodies). The fused cells
are transferred to a medium that is selective for fused cells.
Several cell cultures are then grown from single parent cells. The
antibodies from the different parent cells are then assayed using
well-known methods such as ELISA to determine the antibodies
ability to bind the antigen.
[0043] It would be understood by those skilled in the art, that the
systematic evolution of ligands by exponential enrichment (SELEX)
technique, or similar techniques, could be used to produce aptamers
that specifically bind or target compounds or cells. In the SELEX
technique, a large quantity of randomly generated sequences is
generated and exposed to the target ligand. The sequences that did
not bind the target ligand are removed through affinity
chromatography. The sequences that did bind the target ligand are
then eluted and amplified by PCR to prepare for subsequent rounds
of selection, in order to find the sequence that binds best to the
ligand.
* * * * *
References