System for determining the accuracy of serially-connected drug modules in a combined drug delivery device using voltage

Abstract

Provided herein is a combination drug delivery device comprising: a plurality of modules connectable in series, each module comprising at least one drug component; and a main controller. Each module comprises: a power line; a ground line; a multiplexer having a plurality of identified input channels, at least a subset of which are selectively connected to one of the power line and the ground line; a first digital logic line configured to select the input channel; a voltage reference line having a first resistor corresponding to the output of the multiplexer; and a branch line connected to the voltage reference line, the branch line having a normally closed switch for connecting the branch line to the ground line, the switch being opened by connection to another module. The main controller sequentially selects the input channels with the same identification on all the modules and measures the reference voltage across all the modules.

Description

Background Art

[0001] Combination drug delivery devices and systems are shown and described in: U.S. Provisional Patent Application No. 62 / 670,266, filed May 11, 2018; PCT Application No. PCT / US2019 / 031727, filed May 10, 2019; PCT Application No. PCT / 2019 / 031762, filed May 10, 2019; and PCT Application No. PCT / US2019 / 031791, filed May 10, 2019. All of the above-mentioned patent applications belong to the same assignee as herein. As shown in the above-mentioned patent applications, drug modules of different liquid drugs can be provided in various combinations to provide different (personalized) drug combinations. The drug modules can be nested (i.e., connected) in series or in parallel on a tray or other infrastructure. Alternatively, the drug modules can be directly connected to each other in series (vertically and / or horizontally). U.S. Provisional Patent Application No. 62 / 670,266, PCT Application No. PCT / US2019 / 031727, PCT Application No. PCT / 2019 / 031762, and PCT Application No. PCT / US2019 / 031791 are incorporated herein by reference in their respective entireties.

[0002] The advantage of a serially connected modular system over a nested design is that it does not require a separate pallet assembly for fluid connections, making it more efficient in terms of components and therefore supply chain.

[0003] In a nested system, the tray design can "store" information about the correct configuration of modules through the inherent design and layout of the tray design. For example, the tray can provide a configuration (e.g., mechanical mating features such as a "lock and key" feature) that ensures that only the correct medication modules can be inserted into the tray nest and that the correct medication modules are arranged in the correct order. This acts as a safety check when preparing the medication modules for use. In contrast, a serially connected system does not have a tray-like component and therefore lacks the ability to perform safety checks based on this.

[0004] Because tray-based error prevention mechanisms are not possible with serial connections, it is desirable to provide other devices in the serially connected system to detect configuration errors and thereby prevent medication errors from occurring. Summary of the Invention

[0005] Provided herein is a combination drug delivery device comprising: a plurality of modules connectable in series, each of the modules comprising at least one drug component; and a main controller having a power supply and a ground. Each of the modules comprises: a power supply line, wherein, in the case of the modules being connected in series, the power supply line is connected in series between the modules, the power supply line connected in series being connected to the power supply; a ground line, wherein, in the case of the modules being connected in series, the ground line is connected in series between the modules, the ground line connected in series being connected to the ground; a multiplexer having a plurality of identified input channels and a single output, wherein at least a subset of the input channels are selectively connected to one of the power supply line and the ground line of the corresponding module; a first digital logic line, the first digital logic line being configured to select the input channel, wherein, in the case of the modules being connected in series, The main controller includes a first digital logic line connected in series between the modules, the first logic line connected in series connected to the main controller; a voltage reference line having a first resistor of a known value corresponding to the output of the multiplexer and a second resistor of a known value connected in parallel with the first resistor, wherein, when the modules are connected in series, the voltage reference line is connected in series between the modules and the main controller is connected; and a branch line connected to the voltage reference line, the branch line having a third resistor of a known value and a normally closed switch thereon to connect the branch line to the ground line, the switch being opened by connection to another module. The main controller sequentially selects identically identified input channels on all the modules using the first digital logic line and measures a reference voltage across all the modules for each of the identically identified input channels. Advantageously, the measured reference voltage can be used to identify a binary code associated with the module, thereby providing an indication of the contents of each module and the module sequence.

[0006] These and other features of the present invention will be better understood through a study of the detailed description and accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Figure 1-13B Various features of devices formed in accordance with the present invention are depicted. DETAILED DESCRIPTION

[0008] refer to Figure 1-Figure 3, shows an arrangement that can be used to verify the accuracy of multiple serially connected drug modules 12 of a combination drug delivery device 14. Each drug module 12 includes a drug reservoir 16 for accommodating a liquid drug 18. The drug reservoir 16 can be defined by a portion of the drug module 12, or by a component such as a vial inserted into the drug module 12. The combination drug delivery device 14, including any aspects thereof, can be formed according to any embodiment disclosed in any of U.S. Provisional Patent Application No. 62 / 670,266, PCT Application No. PCT / US2019 / 031727, PCT Application No. PCT / 2019 / 031762, and PCT Application No. PCT / US2019 / 031791. For illustrative purposes, exemplary features of the combination drug delivery device 14 are described herein. As will be appreciated by those skilled in the art, the present invention can be used for any combination drug delivery device disclosed in any of the above-mentioned patent applications, including any element thereof (e.g., system, drug module 12, means for connecting drug module 12, flow controller 34, etc.).

[0009] like Figure 1 As shown, the drug modules 12 are connected in series so that a single flow path is defined for the drug delivery device 14 through the series of drug modules 12, through which the liquid drug 18 of each drug module 12 can be drawn. Figure 1 As shown, an inlet tube 20 and an outlet tube 22 may be provided for each drug module 12 so that the liquid drug 18 may be drawn out sequentially from each drug module 12. Figure 3 As shown, the inlet tube 20 and the outlet tube 22 may be formed continuously between the drug reservoirs 16 such that the length of tube provided serves as both the outlet of one drug reservoir 16 and the inlet of the next drug reservoir 16 . Figure 1 Six medication modules 12 (12A-12F) are shown. As will be appreciated by those skilled in the art, any number of medication modules 12 may be utilized. A vent 13v may be provided at the end of the flow path (in the final medication module).

[0010] Note that a series of one or more bypass medication modules 12BY may be required to accommodate empty positions in the series, but not contain any liquid medication. Figure 2 As shown, the bypass drug module 12BY may have a bypass tube 24 extending from its inlet to its outlet to allow flow therethrough without a drug reservoir. Figure 3 As shown, a bypass tube 24 may be provided in place of one medication module 12 to connect two components of the drug delivery device 14 , such as two medication modules 12 or one medication module 12 and a controller housing described below.

[0011] The type and concentration of the liquid medication 18 contained in the medication modules 12 can vary. The liquid medication 18 in some modules 12 can be a diluent without a pharmaceutically active agent or a biologically active agent. The medication modules 12 can contain one or more solid components that can be reconstituted by a flow of diluent therein to form a liquid medication. The ability of the serially connected medication modules 12 to contain a variety of medication types and concentrations allows the drug delivery device 14 to be a combination medication delivery device 14, thereby providing a mix of various liquid medications. The specific combination of liquid medications 18 intended for a patient is prescribed by a physician. The present invention provides confirmation of the accuracy of the inclusion of specific medication modules 12 in the medication delivery device 14 and the order in which the medication modules 12 are included. The order of the medication modules 14 can be important and may have an impact on the efficacy of the resulting combination.

[0012] The drug delivery device 14 preferably includes a controller housing 26 to which the serially connected drug modules 12 are connected. The outlet tube 22 of the first drug module 12A (closest to the controller housing 26) communicates with an inlet 28 formed in the controller housing 26, into which the liquid drug 18 can flow from the drug module 12. A delivery tube 30 extends from the inlet 28 to deliver the liquid drug 18 through the controller housing 26 to an outlet 32. A tube or delivery tool can be secured to the outlet 32 to direct the liquid drug 18 to a storage device (e.g., an IV bag, a syringe) or to a drug delivery device connected to the patient (e.g., a butterfly needle).

[0013] A flow controller 34 is provided in the controller housing 26 that selectively regulates the flow through the delivery tube 30. In one embodiment, the flow controller 34 can include a drivable negative pressure source 36 (e.g., a pump) provided in the controller housing 26 to aspirate the liquid drug 18 through the delivery tube 30 (which can be discontinuous) through the inlet 28 and discharge the liquid drug 18 through the outlet 32. In a static state, the negative pressure source 36 does not generate negative pressure and therefore does not aspirate the liquid drug 18. In a further embodiment, the flow controller 34 can include one or more adjustable valves 38 provided in the controller housing 26 that are configured to selectively regulate the flow through the delivery tube 30, and in particular, are configured to selectively adjust between an open state and a closed state, such as a ball valve. By using the valves 38, a negative pressure source external to the controller housing 26 can be utilized that is configured to apply negative pressure to the outlet 32 to aspirate the liquid drug 18 therefrom.

[0014] A control unit 40 may be provided in the controller housing 26 and include a computing processing unit (CPU) 42. Preferably, the flow controller 34 is electrically driven to be controlled by the CPU 42. For example, a motor or actuator may be provided with a switch configured to be controlled by the CPU 42. Actuation of the motor may cause the negative pressure source 30 to be activated (e.g., the pump is turned on), while actuation of the actuator may cause the valve 38 to be adjusted to an open state (e.g., the valve stem is rotated to an open state). The CPU 42 may adjust the switch to a closed position to turn off the motor or close the valve.

[0015] It is envisioned that the drug modules 12 will be connected in series when ready for use. Therefore, the user or a representative of the user will need to assemble the drug modules 12. As a fail-safe mechanism, to ensure that the drug modules 12 are properly contained in the drug delivery device 14 in the correct order, each drug module 12 can have a circuit therein that represents the drug 18 contained in the drug module 12. The circuit can be multiple binary input channels of a multiplexer, and the power / ground state of the input channels defines individual binary cells that can be grouped together to provide a binary cell string to each module. The binary cell string can specify the type of drug and possibly the concentration or strength of the drug. The liquid drug 18 can be loaded into the drug module 12 in a manufacturing facility or pharmacy, while the input channels are adjusted to the on / off (power / ground position) on the module 12. Care is required to configure the input channels in the drug module 12.

[0016] The specific liquid medication 18 (type, concentration) will be specified by the prescription. The medication module 12 will be ready to contain the specified liquid medication 18—the number of medication modules 12 to be used will be at least equal to the number of medication components specified by the prescription. The medication module 12, along with the controller housing 26, can be delivered as a kit to the user or a location associated with the user for assembly. Instructions for assembling the medication modules 12 will be provided, including the order of the medication modules 12, such as first position (closest to the controller housing 26), second position, etc.

[0017] refer to Figure 4-Figure 6, each module 12 is provided with three resistors 1a, 1b, 1c of known values. Preferably, the resistance value of resistor 1c (marked as 2R resistor) is twice that of resistors 1a, 1b (marked as R resistor). One side of resistor 1c is connected to the output of an analog multiplexer 2, which connects one of several input channels 3a, 3b, 3c, 3d to a single output. The desired channel 3a, 3b, 3c, 3d is selected by one or more digital logic lines 4. In this application, the multiplexer 2 transmits the voltage from one of the four input channels 3a, 3b, 3c, 3d. One of these input channels (3a) can be connected to a power supply, while the remaining channels 3b, 3c, 3d are connected to a power supply or ground via switches. These switches are configured to represent a binary cell string of the liquid drug 18 of the corresponding module 12. The switch can be in the form of one or more of the following: a hardware jumper, a resistor short circuit, or a small SPDT switch.

[0018] Figure 4-Figure 6 Three switches are shown, but more are possible. The following formula relates to the number of possible unique drug IDs (D) (ie, binary cell strings) that can be configured based on the number of multiplexer channels (N):

[0019] D=2N-1.

[0020] The index N-1 is used to account for the fact that one input channel of the multiplexer 2 can, in a preferred embodiment, be connected directly to a power supply rather than a switch. As discussed below, this allows the number of modules 12 connected in series to be determined without prior notice.

[0021] The multiplexer is controlled by at least one binary logic line 4. Each binary combination of the logic states of the logic line 4 indicates which of the multiplexer 2 input channels 3b, 3c, 3d should be passed to the multiplexer 2 output. The number of multiplexer select lines (S) (i.e., logic lines 4) is related to the number of channels (N) as follows:

[0022] N=2S.

[0023] exist Figure 4-Figure 6 In the example, S=2 selection lines (logic line 4) correspond to 2 2 = 4 multiplexer channels 3a, 3b, 3c, 3d, but this value can be doubled for each additional select line. This relationship means that the number of possible unique drug IDs is related to the number of select lines by the following formula:

[0024] D=2^[(2^S)-1].

[0025] This relationship suggests that by adding a few select lines, a virtually unlimited number of drug IDs can be encoded. Table 1 below illustrates this concept. Switches 3b, 3c, and 3d can take the form of resistor shorts or frangible copper traces, both of which are inexpensive and have a low profile, meaning that a switch count of 15 or 31 is cost-effective.

[0026] Table 1

[0027]

[0028]

[0029] With the modules 12 connected in series, an analog voltage can be generated across their combined resistor network that corresponds to the binary code for each module. Figure 5 Connections shown.

[0030] The module 12A closest to the controller housing 26 is inserted into operable communication with the control unit 40. Figure 6 As shown, the control unit 40 provides power 25 and ground to module 12A. The next module 12B is inserted into the first module 12A so that connector B of the first module 12A mates with connector A of the second module 12B. The first module 12A then passes power to the second module. This connection scheme continues, so that power from the control unit 40 is connected to all modules 12 connected in series. Similarly, the multiplexer select line 4 is passed to all modules 12, allowing the control unit 40 to globally select which multiplexer channel 3a, 3b, 3c, or 3d of each module 12 is passed to the output of each module's multiplexer 2. The select line 4 is operably linked to the control unit 40 via line 23.

[0031] Once powered on and connected, each module 12 configures an analog resistor network whose output is passed to the next module 12 via the Connector A connection. Conversely, each module 12 accepts analog input from the previous module 12 via the corresponding Connector B connection. The resistor networks of all the series-connected modules 12 combine to form an analog voltage at the output connection of the first module 12A, so that the electronics in the controller housing 26 can read the analog voltage using a standard analog-to-digital converter (ADC) 21. Figure 13A and 13B As shown, connectors A and B may be 8-pin receptacle connectors.

[0032] The resistor connection scheme is based on an electrical architecture commonly known as an R-2R resistor ladder. In order for this circuit to work, the last module in the chain must terminate the resistor ladder to ground via an additional resistor 1a. When a given module 12 has no downstream module (e.g., 12F) connected, its terminating resistor 1a is pulled to ground via an n-channel MOSFET 9, which acts as an electronic switch. The MOSFET 9 is kept on by a pull-up resistor 10 to provide power. When another module 12 is connected, the second module 12 shorts the gate of the MOSFET to ground via connector A, connected to ground 13, thereby disconnecting the first module's terminating resistor 1a from ground. The new module now implements the terminating resistor 1a because it is not connected to its downstream module.

[0033] As discussed above, the control unit 40 can select any one of the N multiplexer input channels 3a, 3b, 3c, 3d by setting a binary code on the S selection lines 4. For a given binary code s, the analog voltage V generated by the M modules can be calculated. 输出(s) Let bms be a binary value indicating whether the switch on multiplexer channel s is connected to power (bms=1) or ground (bms=0), and let V 参考 Indicates the reference voltage:

[0034]

[0035] For example, if M=6 modules are connected together with the switches on their multiplexer channels s configured as 1, 0, 0, 1, 0, and 1, the analog output voltage will be 0.578125 times the reference voltage. A different voltage value can be obtained for each multiplexer select code s, allowing the control unit 40 to cycle through all N multiplexer inputs.

[0036] In addition to the module count, the number of bits of information encoded by this scheme is equal to M(N-1). For example, for the values M=6 and N=4, the scheme encodes a total of 262,144 permutations of drug IDs (from 0 to 7) and module positions (from 1 to 6) for a drug. Increasing the select line count from S=2 to S=3 (and therefore the multiplexer channel count from N=4 to N=8) increases the range of drug IDs to 0 to 127, and the total permutation count increases to over 4 trillion.

[0037] Note, however, that the above output voltage formula requires the control unit 40 to know the module count M. In an alternative embodiment, the electronics can determine the number of modules 12 themselves by dedicating one multiplexer input (e.g., 3a) on each module 12 to power. In this way, when the multiplexer channel is selected, the output voltage V 计数 corresponds to the module count and will be equal to:

[0038]

[0039] For example, if the voltage read by the control unit 40 is 0.875 times the reference voltage, it can be determined that the connected module count is 3, because 1 / 2+1 / 4+1 / 8=0.875. Similarly, a module count of 6 generates a voltage that is 0.984375 times the reference voltage.

[0040] Figure 6 A full stack of six modules 12 is shown, with the control electronics in the controller housing 26. The control unit 40 has a power supply 25 (such as a battery) that is passed through to all the modules 12 connected in series. The control unit 40 (which can be a microcontroller, CPLD, or FPGA running embedded firmware) sets the multiplexer channel select line 23 to a given value (which is then transmitted via the select line 4) and then reads the resulting analog voltage from the module via the analog-to-digital converter (ADC) 21. The control unit 40 then updates the multiplexer channel select line 23 to the next binary value, reads the next analog voltage, and continues until an analog voltage has been obtained for each multiplexer channel 3a, 3b, 3c, 3d on all modules 12. From these voltages, the control unit 40 can use the V 输出(s) and V 计数 The relationship between the number of connected modules 12 and the binary drug ID of each module 12 is determined (in Figure 6 In Chinese: b11, b12, b13 of module 1; b21, b22, 23 of module 2, etc.).

[0041] Figure 7-Figure 8 Different reference voltages representing different binary code readings for different input channels of the multiplexer 2 of the module 12 are shown. Figure 7 In the top row, V 输出 =0.75*V 参考 , which represents a binary cell string starting with 11, corresponding to both modules at that input channel having a powered state. In contrast, in the second row, the left module has a grounded input channel and the right module has a powered input channel, resulting in a 10 binary reading. The bottom row has the opposite powered and grounded states from the second row and therefore produces a 01 reading. By arranging these readings, the binary cell string of the left module reads 101 (from bottom to top), while the right module reads 011. Therefore, the binary cell string of each module 12 can be identified together with the order of the modules 12. Figure 8 Five modules with the same working principle are presented.

[0042] Figures 9-12The available voltage ratios are provided as an indication of the different binary cell strings. By measuring the analog voltages as discussed above, the binary cell string for each input channel can be determined and then combined to identify the drug ID and sequence for each module 12.

[0043] Figure 13A and 13B Possible printed circuit board (PCB) circuit arrangements that may be used in each module 12 are shown.

[0044] The binary string of each module 12 can be placed in order to generate an activation code. The activation code can be used to compare with the verification code to determine its accuracy. In one embodiment, the verification code can be stored in a non-transitory memory 41 associated with the CPU 42 in the controller housing 26. Alternatively, the verification code can be transmitted to the CPU 42 (e.g., via a receiver on the controller housing 26), and the CPU 42 runs a comparison to determine a match. In the event of a match between the activation code and the verification code, the CPU 42 can actuate the flow controller 34 to enable delivery of the liquid drug 18.

[0045] The flow controller 34 can be provided with a storage (i.e., deactivated) state, for example, in which one or more adjustable valves 38 are in a closed position to not allow flow through the delivery tube 30 to reach the outlet 32. Additionally, or alternatively, in the storage state, the negative pressure source 36 is in a static state. When the activation code and the verification code match, as described above, the CPU 42 can actuate the flow controller 34, thereby causing the flow controller 34 to enter the use state. When the flow controller 34 is in the use state, delivery of the liquid drug 18 from the drug delivery device 14 can be achieved. Specifically, one or more adjustable valves 38 can be adjusted to an open position to allow flow through the delivery tube 30 to reach the outlet 32. Additionally, the negative pressure source 36 can be actuated, or alternatively, can be placed in an activated state, awaiting actuation (e.g., by a switch on the controller housing 26).

[0046] In one embodiment, any combination drug delivery device disclosed herein can deliver two or more drugs to benefit patients suffering from any of a variety of diseases or conditions (e.g., cancer, autoimmune disorders, inflammatory disorders, cardiovascular diseases, or fibrotic disorders). In one embodiment, one or more drug modules 12 can include a single drug. In one embodiment, one or more drug modules 12 can include two or more co-prepared drugs. In one embodiment, one or more drug modules 12 can include a drug in solid form (e.g., tablets, capsules, powders, freeze-dried, spray-dried), which can be reconstructed by a diluent stream therein to form a liquid drug.

[0047] In one embodiment, one or more of the drugs of any combination drug delivery device disclosed herein is an immune checkpoint inhibitor. In certain embodiments, the immune checkpoint inhibitor is a programmed death-1 ("PD-1") pathway inhibitor, a cytotoxic T lymphocyte-associated antigen 4 ("CTLA-4") antagonist, a lymphocyte activation gene-3 ("LAG3") antagonist, a CD80 antagonist, a CD86 antagonist, a T cell immunoglobulin and mucin domain ("Tim-3") antagonist, a T cell immunoreceptor with Ig and ITIM domains ("TIGIT") antagonist, a CD20 antagonist, a CD96 antagonist, an indoleamine 2,3-dioxygenase ("IDO1") antagonist, a stimulator of interferon genes ("STING") antagonist, a GARP antagonist, a CD40 antagonist, an adenosine A2A receptor ("A2aR") antagonist, a CEACAM1 (CD66a) antagonist, a CEA antagonist, a CD47 antagonist, a receptor-associated immunoglobulin domain-containing protein ("R ... CD20 antagonist, a CD96 antagonist, a T cell immunoreceptor with Ig and ITIM domains ("TIGIT") antagonist, a CD20 antagonist, a CD96 antagonist, a T cell immunoreceptor with Ig and ITIM domains ("T2aR") antagonist, a CD20 antagonist, a CD96 antagonist, a T cell immunoreceptor with Ig and ITIM domains ("T2aR") antagonist, a CD20 antagonist, a CD20 antagonist, a CD2 Immunoglobulin Domain Containing Protein, "PVRIG") antagonists, tryptophan 2,3-dioxygenase ("TDO") antagonists, V-domain Ig inhibitor of T cell activation ("VISTA") antagonists, or killer cell immunoglobulin-like receptor ("KIR") antagonists.

[0048] In one embodiment, the PD-1 pathway inhibitor is an anti-PD-1 antibody or an antigen-binding fragment thereof. In certain embodiments, the anti-PD-1 antibody is pembrolizumab (KEYTRUDA; MK-3475), pidilizumab (CT-011), nivolumab (OPDIVO; BMS-936558), PDR001, MEDI0680 (AMP-514), TSR-042, REGN2810, JS001, AMP-224 (GSK-2661380), PF-06801591, BGB-A317, BI 754091, or SHR-1210.

[0049] In one embodiment, the PD-1 pathway inhibitor is an anti-PD-L1 antibody or an antigen-binding fragment thereof. In certain embodiments, the anti-PD-L1 antibody is atezolizumab (TECENTRIQ; RG7446; MPDL3280A; RO5541267), durvalumab (MEDI4736), BMS-936559, avelumab (bavencio), LY3300054, CX-072 (Proclaim-CX-072), FAZ053, KN035, or MDX-1105.

[0050] In one embodiment, the PD-1 pathway inhibitor is a small molecule drug. In certain embodiments, the PD-1 pathway inhibitor is CA-170. In another embodiment, the PD-1 pathway inhibitor is a cell-based therapy. In one embodiment, the cell-based therapy is a PD-L1 / L2-silenced dendritic cell vaccine loaded with MiHA. In other embodiments, the cell-based therapy is an anti-programmed cell death protein 1 antibody expressing multipotent killer T lymphocytes, autologous PD-1-targeting chimeric switch receptor-modified T lymphocytes, or PD-1-knocked-out autologous T lymphocytes.

[0051] In one embodiment, the PD-1 pathway inhibitor is an anti-PD-L2 antibody or an antigen-binding fragment thereof. In another embodiment, the anti-PD-L2 antibody is rHIgM12B7.

[0052] In one embodiment, the PD-1 pathway inhibitor is a soluble PD-1 polypeptide. In certain embodiments, the soluble PD-1 polypeptide is a fusion polypeptide. In some embodiments, the soluble PD-1 polypeptide comprises a ligand-binding fragment of the extracellular domain of PD-1. In other embodiments, the soluble PD-1 polypeptide comprises a ligand-binding fragment of the extracellular domain of PD-1. In another embodiment, the soluble PD-1 polypeptide further comprises an Fc domain.

[0053] In one embodiment, the immune checkpoint inhibitor is a CTLA-4 antagonist. In certain embodiments, the CTLA-4 antagonist is an anti-CTLA-4 antibody or an antigen-binding fragment thereof. In some embodiments, the anti-CTLA-4 antibody is ipilimumab (YERVOY), tremelimumab (tremelimumab) (ticilimumab; CP-675,206), AGEN-1884 or ATOR-1015. In one embodiment, any combination drug delivery device disclosed herein includes a CTLA-4 antagonist, such as ipilimumab (YERVOY); and a PD-1 pathway inhibitor, such as nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA).

[0054] In one embodiment, the immune checkpoint inhibitor is an antagonist of LAG3. In certain embodiments, the LAG3 antagonist is an anti-LAG3 antibody or an antigen-binding fragment thereof. In certain embodiments, the anti-LAG3 antibody is relatlimab (BMS-986016), MK-4280 (28G-10), REGN3767, GSK2831781, IMP731 (H5L7BW), BAP050, IMP-701 (LAG-5250), IMP321, TSR-033, LAG525, BI 754111 or FS-118. In one embodiment, any combination drug delivery device disclosed herein includes a LAG3 antagonist, such as relatlimab or MK-4280; and a PD-1 pathway inhibitor, such as nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA). In one embodiment, any combination drug delivery device disclosed herein includes a LAG3 antagonist, such as relalizumab or MK-4280; and a CTLA-4 antagonist, such as ipilimumab (YERVOY).

[0055] In one embodiment, any combination drug delivery device disclosed herein includes a LAG3 antagonist, such as relalizumab or MK-4280; a CTLA-4 antagonist, such as ipilimumab (YERVOY); and a PD-1 pathway inhibitor, such as nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA).

[0056] In one embodiment, the immune checkpoint inhibitor is a KIR antagonist. In certain embodiments, the KIR antagonist is an anti-KIR antibody or an antigen-binding fragment thereof. In some embodiments, the anti-KIR antibody is lirilumab (1-7F9, BMS-986015, IPH 2101) or IPH4102.

[0057] In one embodiment, the immune checkpoint inhibitor is a TIGIT antagonist. In one embodiment, the TIGIT antagonist is an anti-TIGIT antibody or an antigen-binding fragment thereof. In certain embodiments, the anti-TIGIT antibody is BMS-986207, AB 154, COM902 (CGEN-15137), or OMP-313M32.

[0058] In one embodiment, the immune checkpoint inhibitor is a Tim-3 antagonist. In certain embodiments, the Tim-3 antagonist is an anti-Tim-3 antibody or an antigen-binding fragment thereof. In some embodiments, the anti-Tim-3 antibody is TSR-022 or LY3321367.

[0059] In one embodiment, the immune checkpoint inhibitor is an IDO1 antagonist. In another embodiment, the IDO1 antagonist is indoximod (NLG8189; 1-methyl-D-TRP), icandrostat (INCB-024360, INCB-24360), KHK2455, PF-06840003, navoximod (RG6078, GDC-0919, NLG919), BMS-986205 (F001287), or a pyrrolidine-2,5-dione derivative.

[0060] In one embodiment, the immune checkpoint inhibitor is a STING antagonist. In certain embodiments, the STING antagonist is a 2' or 3'-monofluoro-substituted cyclic dinucleotide; a 2'3'-difluoro-substituted mixed-bond 2',5'–3',5' cyclic dinucleotide; a 2'-fluoro-substituted bis-3',5' cyclic dinucleotide; a 2',2"-diF-Rp,Rp,bis-3',5' cyclic dinucleotide; or a fluorinated cyclic dinucleotide.

[0061] In one embodiment, the immune checkpoint inhibitor is a CD20 antagonist. In some embodiments, the CD20 antagonist is an anti-CD20 antibody or an antigen-binding fragment thereof. In one embodiment, the anti-CD20 antibody is rituximab (RITUXAN; IDEC-102; IDEC-C2B8), ABP 798, ofatumumab, or obinutuzumab.

[0062] In one embodiment, the immune checkpoint inhibitor is a CD80 antagonist. In certain embodiments, the CD80 antagonist is an anti-CD80 antibody or an antigen-binding fragment thereof. In one embodiment, the anti-CD80 antibody is galiximab or AV 1142742.

[0063] In one embodiment, the immune checkpoint inhibitor is a GARP antagonist. In some embodiments, the GARP antagonist is an anti-GARP antibody or an antigen-binding fragment thereof. In certain embodiments, the anti-GARP antibody is ARGX-115.

[0064] In one embodiment, the immune checkpoint inhibitor is a CD40 antagonist. In certain embodiments, the CD40 antagonist is an anti-CD40 antibody or its antigen-binding fragment. In some embodiments, the anti-CD40 antibody is BMS3h-56, lucatumumab (lucatumumab) (HCD122 and CHIR-12.12), CHIR-5.9 or dacetuzumab (dacetuzumab) (huS2C6, PRO 64553, RG 3636, SGN 14, SGN-40). In another embodiment, the CD40 antagonist is a soluble CD40 ligand (CD40-L). In one embodiment, the soluble CD40 ligand is a fusion polypeptide. In one embodiment, the soluble CD40 ligand is CD40-L / FC2 or monomeric CD40-L.

[0065] In one embodiment, the immune checkpoint inhibitor is an A2aR antagonist. In some embodiments, the A2aR antagonist is a small molecule. In certain embodiments, the A2aR antagonist is CPI-444, PBF-509, istradefylline (KW-6002), preladenant (SCH420814), tozadenant (SYN115), vipadenant (BIIB014), HTL-1071, ST1535, SCH412348, SCH442416, SCH58261, ZM241385 or AZD4635.

[0066] In one embodiment, the immune checkpoint inhibitor is a CEACAM1 antagonist. In some embodiments, the CEACAM1 antagonist is an anti-CEACAM1 antibody or an antigen-binding fragment thereof. In one embodiment, the anti-CEACAM1 antibody is CM-24 (MK-6018).

[0067] In one embodiment, the immune checkpoint inhibitor is a CEA antagonist. In one embodiment, the CEA antagonist is an anti-CEA antibody or an antigen-binding fragment thereof. In certain embodiments, the anti-CEA antibody is cergutuzumab amunaleukin (RG7813, RO-6895882) or RG7802 (RO6958688).

[0068] In one embodiment, the immune checkpoint inhibitor is a CD47 antagonist. In some embodiments, the CD47 antagonist is an anti-CD47 antibody or an antigen-binding fragment thereof. In certain embodiments, the anti-CD47 antibody is HuF9-G4, CC-90002, TTI-621, ALX148, NI-1701, NI-1801, SRF231, or Effi-DEM.

[0069] In one embodiment, the immune checkpoint inhibitor is a PVRIG antagonist. In certain embodiments, the PVRIG antagonist is an anti-PVRIG antibody or an antigen-binding fragment thereof. In one embodiment, the anti-PVRIG antibody is COM701 (CGEN-15029).

[0070] In one embodiment, the immune checkpoint inhibitor is a TDO antagonist. In one embodiment, the TDO antagonist is a 4- (indole -3- base) -pyrazole derivative, a 3- indole substituted derivative or a 3- (indole -3- base) -pyridine derivative. In another embodiment, the immune checkpoint inhibitor is an IDO and TDO dual antagonist. In one embodiment, the IDO and TDO dual antagonist is a small molecule.

[0071] In one embodiment, the immune checkpoint inhibitor is a VISTA antagonist. In some embodiments, the VISTA antagonist is CA-170 or JNJ-61610588.

[0072] In one embodiment, one or more of the drugs of any combination drug delivery device disclosed herein is an immune checkpoint enhancer or stimulator.

[0073] In one embodiment, the immune checkpoint enhancer or stimulator is a CD28 agonist, a 4-1BB agonist, an OX40 agonist, a CD27 agonist, a CD80 agonist, a CD86 agonist, a CD40 agonist, an ICOS agonist, a CD70 agonist, or a GITR agonist.

[0074] In one embodiment, the immune checkpoint enhancer or stimulator is an OX40 agonist. In certain embodiments, the OX40 agonist is an anti-OX40 antibody or an antigen-binding fragment thereof. In some embodiments, the anti-OX40 antibody is tavolixizumab (MEDI-0562), pogalizumab (MOXR0916, RG7888), GSK3174998, ATOR-1015, MEDI-6383, MEDI-6469, BMS 986178, PF-04518600 or RG7888 (MOXR0916). In another embodiment, the OX40 agonist is a cell-based therapy. In certain embodiments, the OX40 agonist is a GINAKIT cell (T lymphocyte expressing iC9-GD2-CD28-OX40).

[0075] In one embodiment, the immune checkpoint enhancer or stimulator is a CD40 agonist. In some embodiments, the CD40 agonist is an anti-CD40 antibody or an antigen-binding fragment thereof. In one embodiment, the anti-CD40 antibody is ADC-1013 (JNJ-64457107), RG7876 (RO-7009789), HuCD40-M2, APX005M (EPI-0050) or Chi Lob 7 / 4. In another embodiment, the CD40 agonist is a soluble CD40 ligand (CD40-L). In one embodiment, the soluble CD40 ligand is a fusion polypeptide. In certain embodiments, the soluble CD40 ligand is a trimeric CD40-L

[0076] In one embodiment, the immune checkpoint enhancer or stimulator is a GITR agonist. In certain embodiments, the GITR agonist is an anti-GITR antibody or its antigen-binding fragment. In one embodiment, the anti-GITR antibody is BMS-986156, TRX518, GWN323, INCAGN01876 or MEDI1873. In one embodiment, the GITR agonist is a soluble GITR ligand (GITRL). In some embodiments, the soluble GITR ligand is a fusion polypeptide. In another embodiment, the GITR agonist is a cell-based therapy. In one embodiment, the cell-based therapy is an autologous dendritic cell vaccine transfected with anti-CTLA4 mAbRNA / GITRL RNA or an autologous dendritic cell vaccine transfected with GITRL RNA.

[0077] In one embodiment, the immune checkpoint enhancer or stimulator is a 4-1BB agonist. In some embodiments, the 4-1BB agonist is an anti-4-1BB antibody or its antigen-binding fragment. In one embodiment, the anti-4-1BB antibody is urelumab or PF-05082566.

[0078] In one embodiment, immune checkpoint enhancer or stimulator is a CD80 agonist or CD86 agonist. In some embodiments, CD80 agonist or CD86 agonist is soluble CD80 or CD86 ligand (CTLA-4). In certain embodiments, soluble CD80 or CD86 ligand is a fusion polypeptide. In one embodiment, CD80 or CD86 ligand is CTLA4-Ig (CTLA4-IgG4m, RG2077 or RG1046) or Abatacept (ORENCIA, BMS-188667). In other embodiments, CD80 agonist or CD86 agonist is a cell-based therapy. In one embodiment, cell-based therapy is MGN1601 (allogeneic renal cell carcinoma vaccine).

[0079] In one embodiment, the immune checkpoint enhancer or stimulator is a CD28 agonist. In some embodiments, the CD28 agonist is an anti-CD28 antibody or an antigen-binding fragment thereof. In certain embodiments, the anti-CD28 antibody is TGN1412.

[0080] In one embodiment, the CD28 agonist is a cell-based therapy. In certain embodiments, the cell-based therapy is JCAR015 (anti-CD19-CD28-ζ modified CAR CD3+ T lymphocytes); T lymphocytes expressing CD28CAR / CD137CAR; allogeneic CD4+ memory Th1-like T cells / microparticle-bound anti-CD3 / anti-CD28; autologous T lymphocytes KTE-C19 transduced with anti-CD19 / CD28 / CD3ζCARγ retroviral vectors; anti-CEA IgCD28TCR-transduced autologous T lymphocytes; anti-EGFRvIIICAR-transduced allogeneic T lymphocytes; autologous T lymphocytes expressing CD123CAR-CD28-CD3ζ-EGFRt; autologous T lymphocytes expressing CD171-specific CAR-CD28ζ-4-1-BB-EGFRt; Tcm-enriched autologous T cells expressing CD19CAR-CD28-CD3ζ-EGFRt; autologous PD-1-targeted chimeric switch receptor-modified T lymphocytes (chimera with CD28); expressing CD19CAR-CD2 8-CD3ζ-EGFRt-enriched Tcm T lymphocytes; Tn / mem-enriched T lymphocytes expressing CD19CAR-CD28-CD3ζ-EGFRt; allogeneic T lymphocytes expressing CD19CAR-CD28ζ-4-1BB; autologous T lymphocytes expressing CD19CAR-CD3ζ-4-1BB-CD28; T lymphocytes expressing CD28CAR / CD137CAR; autologous T lymphocytes primed by CD3 / CD28 co-stimulatory vaccine; or T lymphocytes expressing iC9-GD2-CD28-OX40.

[0081] In one embodiment, the immune checkpoint enhancer or stimulator is a CD27 agonist. In certain embodiments, the CD27 agonist is an anti-CD27 antibody or an antigen-binding fragment thereof. In one embodiment, the anti-CD27 antibody is varlilumab (CDX-1127).

[0082] In one embodiment, the immune checkpoint enhancer or stimulator is a CD70 agonist. In some embodiments, the CD70 agonist is an anti-CD70 antibody or an antigen-binding fragment thereof. In one embodiment, the anti-CD70 antibody is ARGX-110.

[0083] In one embodiment, the immune checkpoint enhancer or stimulator is an ICOS agonist. In certain embodiments, the ICOS agonist is an anti-ICOS antibody or an antigen-binding fragment thereof. In some embodiments, the anti-ICOS antibody is BMS986226, MEDI-570, GSK3359609, or JTX-2011. In other embodiments, the ICOS agonist is a soluble ICOS ligand. In some embodiments, the soluble ICOS ligand is a fusion polypeptide. In one embodiment, the soluble ICOS ligand is AMG 750.

[0084] In one embodiment, one or more of the drugs of any combination drug delivery device disclosed herein is an anti-CD73 antibody or antigen-binding fragment thereof. In certain embodiments, the anti-CD73 antibody is MEDI9447.

[0085] In one embodiment, one or more of the drugs of any combination drug delivery device disclosed herein is a TLR9 agonist. In one embodiment, the TLR9 agonist is agatolimod sodium.

[0086] In one embodiment, one or more of the drugs in any combination drug delivery device disclosed herein is a cytokine. In certain embodiments, the cytokine is a member of the chemokine, interferon, interleukin, lymphokine, or tumor necrosis factor family. In some embodiments, the cytokine is IL-2, IL-15, or interferon-γ.

[0087] In one embodiment, one or more of the drugs of any combination drug delivery device disclosed herein is a TGF-β antagonist. In some embodiments, the TGF-β antagonist is fresolimumab (GC-1008); NIS793; IMC-TR1 (LY3022859); ISTH0036; trabedersen (AP 12009); recombinant transforming growth factor-β-2; autologous HPV-16 / 18E6 / E7-specific TGF-β-resistant T lymphocytes; or TGF-β-resistant LMP-specific cytotoxic T lymphocytes.

[0088] In one embodiment, one or more of the drugs in any combination drug delivery device disclosed herein is an iNOS antagonist. In some embodiments, the iNOS antagonist is N-acetylcysteine (NAC), aminoguanidine, L-nitroarginine methyl ester, or S,S-1,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea).

[0089] In one embodiment, one or more of the drugs of any combination drug delivery device disclosed herein is a SHP-1 antagonist.

[0090] In one embodiment, one or more of the drugs of any combination drug delivery device disclosed herein is a colony stimulating factor 1 receptor ("CSF1R") antagonist. In certain embodiments, the CSF1R antagonist is an anti-CSF1R antibody or an antigen-binding fragment thereof. In some embodiments, the anti-CSF1R antibody is emactuzumab.

[0091] In one embodiment, one or more of the drugs of any combination drug delivery device disclosed herein is an agonist of a TNF family member. In some embodiments, the agonist of a TNF family member is ATOR 1016, ABBV-621, or adalimumab.

[0092] In one embodiment, one or more of the drugs of any combination drug delivery device disclosed herein is interleukin 2 (IL-2), such as aldesleukin. Preferably, IL-2 or conjugated IL-2 (e.g., pegylated) has been modified to selectively activate T effector cells relative to T regulatory cells ("T-eff IL-2"), such as bempegaldesleukin. In one embodiment, any combination drug delivery device disclosed herein includes a modified IL-2 that selectively activates T effector cells relative to T regulatory cells, such as bempegaldesleukin; and a PD-1 pathway inhibitor, such as nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA). In one embodiment, any combination drug delivery device disclosed herein includes a modified IL-2 that selectively activates T effector cells relative to T regulatory cells, such as bempegaldesleukin; and a LAG3 antagonist, such as relalizumab or MK-4280. In one embodiment, any combination drug delivery device disclosed herein includes a modified IL-2 that selectively activates T effector cells relative to T regulatory cells, such as benpei aldesleukin; and a PD-1 pathway inhibitor, such as nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA); and a LAG3 antagonist, such as relalizumab or MK-4280. In one embodiment, any combination drug delivery device disclosed herein includes a modified IL-2 that selectively activates T effector cells relative to T regulatory cells, such as benpei aldesleukin; and a CTLA-4 antagonist, such as ipilimumab (YERVOY). In one embodiment, any combination drug delivery device disclosed herein includes a modified IL-2 that selectively activates T effector cells relative to T regulatory cells, such as benpei aldesleukin; a PD-1 pathway inhibitor, such as nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA); and a CTLA-4 antagonist, such as ipilimumab (YERVOY). In one embodiment, any combination drug delivery device disclosed herein includes a modified IL-2 that selectively activates T effector cells relative to T regulatory cells, such as benpei aldesleukin; a CTLA-4 antagonist, such as ipilimumab (YERVOY); and a LAG3 antagonist, such as relalizumab or MK-4280. In one embodiment, any combination drug delivery device disclosed herein includes a modified IL-2 that selectively activates T effector cells relative to T regulatory cells, such as benpei aldesleukin; a PD-1 pathway inhibitor, such as nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA); a CTLA-4 antagonist, such as ipilimumab (YERVOY); and a LAG3 antagonist, such as relalizumab or MK-4280.

[0093] In one embodiment, one or more of the drugs in any combination drug delivery device disclosed herein is a CD160 (NK1) agonist. In certain embodiments, the CD160 (NK1) agonist is an anti-CD160 antibody or an antigen-binding fragment thereof. In one embodiment, the anti-CD160 antibody is BY55.

[0094] In one embodiment, one or more drug modules 12 may include a soluble CTLA-4 polypeptide, which can be used to treat, for example, T cell-mediated autoimmune disorders such as rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, graft-versus-host disease, and transplant rejection. In one embodiment, the soluble CTLA-4 polypeptide is abatacept (ORENCIA), belatacept (NULOJIX), RG2077, or RG-1046. In certain embodiments, one or more drug modules 12 of a combination drug delivery device as described herein include a soluble CTLA-4 polypeptide, such as abatacept (ORENCIA); and a Bruton's tyrosine kinase inhibitor, such as branebrutinib. In certain embodiments, one or more drug modules 12 of a combination drug delivery device as described herein include a soluble CTLA-4 polypeptide, such as abatacept (ORENCIA); and a tyrosine kinase-2 inhibitor, such as BMS-986165. In certain embodiments, one or more drug modules 12 of a combination drug delivery device as described herein include a soluble CTLA-4 polypeptide, such as abatacept (ORENCIA); and interleukin-2 (IL-2) or "T-regIL-2" that selectively activates T regulatory cells as opposed to T effector cells, such as BMS-986326 and NKTR-358.

Claims

1. A combination drug delivery device, comprising: a plurality of modules connectable in series, each of said modules comprising at least one pharmaceutical component; as well as a main controller having a power supply and a ground, Wherein, each of the modules includes: a power line, wherein, when the modules are connected in series, the power line is connected in series between the modules, and the serially connected power line is connected to the power source; a grounding line, wherein, in a case where the modules are connected in series, the grounding line is connected in series between the modules, and the serially connected grounding line is connected to the ground; a multiplexer having a plurality of identified input channels and a single output, wherein at least a subset of the input channels are selectively connected to one of the power line and the ground line of a corresponding module; a first digital logic line configured to select the input channel, wherein, if the modules are connected in series, the first digital logic line is connected in series between the modules, and the serially connected first logic line is connected to the main controller; a voltage reference line having a first resistor of a known value that matches the output of the multiplexer and a second resistor of a known value connected in parallel with the first resistor, wherein, if the modules are connected in series, the voltage reference line is connected in series between the modules, the series-connected voltage reference line being connected to the master controller; a branch line connected to the voltage reference line, the branch line having a third resistor of known value and a normally closed switch thereon to connect the branch line to the ground line, the switch being opened by connection to another module; The main controller uses the first digital logic line to sequentially select input channels with the same identification on all the modules, and measures the reference voltage across all the modules for each of the input channels with the same identification.

2. The combination drug delivery device of claim 1, wherein the switch is an n-channel MOSFET.

3. The combined drug delivery device according to claim 2, wherein each of the modules comprises a second branch line connected to the power line of the corresponding module and the gate of the MOSFET, a fourth resistor being located between the power line and the gate of the MOSFET on the second branch line, wherein The second branch line transmits power to maintain the gate of the MOSFET normally closed.

4. The combined drug delivery device according to claim 3, wherein By being connected to the other module, the second branch line is grounded, causing the gate of the MOSFET to be turned off.

5. The combination drug delivery device of claim 1 , further comprising a second digital logic line configured to select the input channel, wherein When the modules are connected in series, the second digital logic line is connected in series between the modules, and the second logic line of the series connection is connected to the main controller, wherein the main controller selectively uses the first digital logic line and the second digital logic line to sequentially select input channels with the same identification on all the modules, and measures the reference voltage across all the modules for each of the input channels with the same identification.

Images