System for interrogating serially-connected drug modules in a combined drug delivery device

Abstract

In one aspect, the present invention provides a combination drug delivery device, comprising: a plurality of modules that can be connected in series, each of the modules comprising at least one drug component; and a main controller having a computational processing unit. Each of the modules comprises: a non-transitory memory having stored therein an address and an alphanumeric code representing the at least one drug component contained in the corresponding drug module; a sub-controller operably linked to the memory of the corresponding module; and at least one communication bus that can be connected in series with the communication bus of the module connected in series with the corresponding module. The main controller is configured to use the address to sequentially query the sub-controller through the serially connected communication bus to request the code of the corresponding module. Advantageously, the present invention provides a system for confirming the accuracy of the drugs provided with the device and their correct sequencing.

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] In one aspect, the present invention provides a combination drug delivery device, comprising: a plurality of modules that can be connected in series, each of the modules comprising at least one drug component; and a main controller having a computational processing unit. Each of the modules comprises: a non-transitory memory having stored therein an address and an alphanumeric code representing the at least one drug component contained in the corresponding drug module; a sub-controller operably linked to the memory of the corresponding module; and at least one communication bus that can be connected in series with the communication bus of the module connected in series with the corresponding module. The main controller is configured to use the address to sequentially query the sub-controller through the serially connected communication bus to request the code of the corresponding module. Advantageously, the present invention provides a system for confirming the accuracy of the drugs provided with the device and their correct sequencing.

[0006] In a further aspect, there is provided herein 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 computational processing unit. Each of the modules comprises: a non-transitory memory having an alphanumeric code representing at least one drug component contained in the corresponding drug module stored therein; an actuable switch having a normally open position, the switch being actuated to a closed position by connecting the corresponding drug module to another drug module; a sub-controller operably linked to the memory of the corresponding module; and at least one communication bus, the at least one communication bus being connectable in series with a communication bus of a module connected in series with the corresponding module. When the modules are connected in series, each of the sub-controllers determines whether the corresponding switch has been actuated, wherein, after determining that the corresponding switch has not been actuated, the corresponding sub-controller assigns a default address to the corresponding memory, and the default address is transmitted to the main controller. The main controller sequentially issues instructions to the sub-controllers to transmit pulse signals to adjacent modules, and wherein, based on the number of pulse signals received by the modules, the sub-controllers each assign an address to a corresponding memory, and the module address is transmitted to the main controller. The main controller is configured to sequentially poll the sub-controllers using the address to request a code for the corresponding module.

[0007] 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

[0008] Figures 1-6 Various features of devices formed in accordance with the present invention are depicted. DETAILED DESCRIPTION

[0009] 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 10, drug module 12, a method for connecting the drug module 12, a flow controller 34, etc.).

[0010] 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 13 may be provided at the end of the flow path (in the final medication module).

[0011] 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.

[0012] 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.

[0013] 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).

[0014] 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.

[0015] 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.

[0016] It is contemplated that the medication modules 12 will be connected in series when ready for use. Therefore, the user, or someone acting on behalf of the user, will need to assemble the medication modules 12. As a fail-safe mechanism, to ensure that the medication modules 12 are properly contained in the correct order within the drug delivery device 14, each medication module 12 may have an alphanumeric code stored therein representing the medication 18 contained within the medication module 12. The alphanumeric code may specify the medication type and, possibly, the concentration or strength of the medication. The liquid medication 18 may be loaded into the medication module 12 at a manufacturing facility or pharmacy, with the alphanumeric code stored on the module 12. Care must be taken to store the correct alphanumeric code within the medication module 12.

[0017] 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.

[0018] refer to Figure 4 , providing a sub-controller 1 for each module 12, which can be a microprocessor or a programmable logic device. The sub-controller 1 can run embedded firmware to implement the following logic. The sub-controller 1 can access a compact serial communication bus 2, such as I 2C (Inter-Integrated Circuit), as is known in embedded electronics. This interface requires two lines: SCL (Serial Clock) and SDA (Serial Data). In the case where the modules 12 are connected in series, the communication buses 2 of the modules 12 are connected in series to allow communication signals to be passed between the modules 12. In addition, the communication bus 2 of the first medication module 12A is communicatively coupled to the control unit 40 as the main controller. A non-transitory memory 4, such as an address register or other permanent memory, is operably linked to the sub-controller 1 of each module 12. The memory 4 can be programmed with a unique address representing the position of the corresponding module 12 (e.g., the first position of module 12A, the second position of module 12B, etc.). The memory 4 can be used to store an alphanumeric code for the corresponding medication 18. The unique address can also be stored in the memory 4 simultaneously with the alphanumeric code. In the case where the modules 12 are connected in series, as Figure 5 As shown, the control unit 40 can use the unique address to sequentially query the sub-controllers 1 of the modules 12 via the serially connected communication bus 2 to request the stored alphanumeric code for each module 12. The sub-controllers 1 can transmit the alphanumeric code to the control unit 40 via the serially connected communication bus 2. In this way, a small amount of data, on the order of several bytes, can be quickly and compactly communicated to the control unit 40. The alphanumeric codes can be placed in sequence to generate an activation code.

[0019] 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 performs 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 medication 18.

[0020] 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).

[0021] In an alternative embodiment, module 12 may be configured to self-assign a unique address based on its location within device 14 .

[0022] In this embodiment, the module 12 initially does not provide an address in the memory 4. To implement this scheme, each module 12 is provided with an actuable switch 3 (e.g., a mechanical switch) that is preferably normally open. The switch 3 is provided on the module 12 so that it is actuated (i.e., actuated to a closed position) only when another module is connected downstream of the module. In addition, for each module 12, an input line 5a is provided to link with the downstream module 12, and the sub-controller 1 can read the input line, and an output line 5b is provided to link with the upstream module 12, and the sub-controller 1 can control the output line.

[0023] In this embodiment, with modules 12 connected in series, the most downstream module 12 (12F) is the only module whose mechanical switch is not actuated. Therefore, the sub-controller 1 on this module 12 determines that its address should be 1 and assigns itself this address by writing to its memory 4. This address is transmitted to the control unit 40 using the serially connected communication bus 2. The control unit 40 knows that the module 12 with address 1 will automatically assign itself this address and can then communicate freely with this module via the serially connected communication bus 2.

[0024] To establish the addresses of the other modules 12, the control unit 40 sends an instruction to address 1 (i.e., module 12F) telling it to assert its upstream line 5b twice. Module 12F, which has address 1, executes this pulse sequence, which is observed by the next upstream module 12E via its input line 5a. Since it sees two pulses, module 12E can conclude that it must be address 2. Module 12E then writes this address into its memory 4. The control unit 40 then knows that address 2 has been assigned and can communicate freely with that module. Therefore, the control unit 40 issues an instruction to address 2 (i.e., module 12E) to pulse its output line 5b three times. The next module 12D upstream sees this pulse sequence, counts the pulses and concludes that it must be address 3. This process continues until all addresses have been assigned. The control unit 40 can then look up the alphanumeric code for each address as explained above. This address assignment scheme is described in detail in the following sections. Figure 6 They are explained in order.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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).

[0033] 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). 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).

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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).

[0045] 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).

[0046] 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.

[0047] 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).

[0048] 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.

[0049] In one embodiment, the immune checkpoint inhibitor is a VISTA antagonist. In some embodiments, the VISTA antagonist is CA-170 or JNJ-61610588.

[0050] In one embodiment, one or more of the drugs of any combination drug delivery device disclosed herein is an immune checkpoint enhancer or stimulator.

[0051] 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.

[0052] 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).

[0053] 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

[0054] 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.

[0055] 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.

[0056] 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).

[0057] 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.

[0058] 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; autologous T lymphocytes transduced with anti-CEA IgCD28TCR; anti-EGFRvIII CAR-transduced allogeneic T lymphocytes; autologous T lymphocytes expressing CD123CAR-CD28-CD3ζ-EGFRt; autologous T lymphocytes expressing CD171-specific CAR-CD28ζ-4-1-BB-EGFRt; autologous T cells enriched for Tcm expressing CD19CAR-CD28-CD3ζ-EGFRt; autologous PD-1-targeted chimeric switch receptor-modified T lymphocytes (chimera with CD28); enriched for Tcm expressing CD19CAR-CD28-CD3ζ-EGFRt T lymphocytes with Tcm; T lymphocytes enriched for Tn / mem 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.

[0059] 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).

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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).

[0067] In one embodiment, one or more of the drugs of any combination drug delivery device disclosed herein is a SHP-1 antagonist.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] In one embodiment, one or more drug modules 12 may comprise 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.

[0073] 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-reg IL-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 serially connectable modules, each of the modules comprising at least one drug component, wherein the modules are connectable in series to define a single flow path for the drug delivery device; as well as A main controller having a computing processing unit, Each of the modules includes: a non-transitory memory having stored therein an address and an alphanumeric code representing the at least one medication component contained in the corresponding medication module; a secondary controller operatively linked to the memory of the corresponding module; at least one communication bus that is connectable in series with a communication bus of a module connected in series with a corresponding module, wherein, in the case where the modules are connected in series, the communication buses of the serially connected modules allow communication signals to be directly transferred between the modules, The main controller is configured to use the address to sequentially query the secondary controllers through the serially connected communication bus to request the code of the corresponding module. 2 . The combination drug delivery device according to claim 1 , wherein the main controller is configured to place the received codes of the corresponding modules in order to generate an activation code. 3 . The combination drug delivery device of claim 2 , wherein the main controller is configured to compare the generated activation code with a verification code.

4. The combination drug delivery device of claim 3, further comprising an actuatable flow controller for selectively adjusting the flow of the at least one drug component, wherein The main controller is configured to actuate the flow controller if the generated activation code and the verification code match.

5. The combined drug delivery device according to claim 4, wherein Upon actuation, the flow controller causes at least one of: adjusting one or more adjustable values; actuating a negative pressure source; And placing the negative pressure source in an activated state waiting for actuation.

6. 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 computing processing unit, Each of the modules includes: a non-transitory memory having stored therein an alphanumeric code representing the at least one medication component contained in the corresponding medication module; an actuatable switch having a normally open position, the switch being actuated to a closed position by connecting the corresponding medication module with another medication module; a secondary controller operatively linked to the memory of the corresponding module; at least one communication bus connectable in series with a communication bus of a module connected in series with the corresponding module, wherein, in a case where the modules are connected in series, each of the sub-controllers determines whether a corresponding switch has been actuated, wherein, upon determining that the corresponding switch has not been actuated, the corresponding sub-controller assigns a default address to a corresponding memory, and the default address is transmitted to the main controller, wherein the main controller sequentially issues instructions to the sub-controllers to transmit pulse signals to adjacent modules, and wherein, based on the number of pulse signals received by the module, the sub-controllers each assign an address to a corresponding memory, and the address of the module is transmitted to the main controller, The main controller is configured to use the address to query the secondary controller one by one to request the code of the corresponding module. 7 . The combination drug delivery device according to claim 6 , wherein the main controller is configured to place the received codes of the corresponding modules in order to generate an activation code.

8. The combination drug delivery device of claim 7, wherein the main controller is configured to compare the generated activation code with a verification code.

9. The combination drug delivery device of claim 8, further comprising an actuatable flow controller for selectively adjusting the flow of the at least one drug component, wherein The main controller is configured to actuate the flow controller if the generated activation code and the verification code match.

10. The combination drug delivery device according to claim 9, wherein Upon actuation, the flow controller causes at least one of: adjusting one or more adjustable values; actuating a negative pressure source; And placing the negative pressure source in an activated state waiting for actuation.

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