RADIALLY ADJUSTABLE MULTI-CARTRIDGE COMBINATORIAL DRUG DELIVERY DEVICE FOR SUBCUTANEOUS INJECTION

Abstract

In one aspect, a drug delivery device is provided for delivering drug from a plurality of drug cartridges. The drug delivery device includes: a cylindrical cassette configured to accommodate the plurality of drug cartridges; a reversibly advanceable plunger; and, an indexer for incrementally rotating the cassette to align the plurality of drug cartridges individually with the plunger. The indexer includes first and second shafts with cooperating elements which cause incremental rotation of the first shaft, relative to the second shaft, upon the second shaft engaging the first shaft.

Claims

1. A drug delivery device for delivering drug from a plurality of drug cartridges to a patient, each of the drug cartridges including an elongated body having a first end sealed with a septum and a second open end, and, a stopper located in the body, wherein, in an initial state, each of the drug cartridges includes at least one drug contained in the body between the stopper and the septum thereof, the drug delivery device comprising: a cylindrical cassette configured to accommodate the plurality of drug cartridges; a plurality of cannulas positioned to simultaneously pierce the septa of the plurality of drug cartridges; a plurality of fluidic channels individually connected to the plurality of cannulas, the plurality of fluidic channels converging to a common outlet; a reversibly advanceable plunger; and, an indexer for incrementally rotating the cassette to align the plurality of drug cartridges individually with the plunger, the plunger being advanceable to urge the stopper of the aligned drug cartridge towards the septum of the aligned drug cartridge to cause the at least one drug contained in the body of the aligned drug cartridge to be expelled through the cannula piercing the septum of the aligned drug cartridge.

2. (canceled)

3. A drug delivery device as in claim 11, wherein the indexer further includes a tubular carrier, the first and second shafts extending into the carrier.

4. A drug delivery device as in claim 3, wherein the carrier includes a plurality of notches defined on an inner surface thereof, wherein the first shaft includes a plurality of slant-cut teeth formed to interface with the plurality of notches, and, wherein the first shaft is biased to have the slant-cut teeth normally interface with the plurality of notches.

5. A drug delivery device as in claim 4, wherein the second shaft includes a plurality of teeth, wherein, with the axial shifting of the second shaft relative to the first shaft, the plurality of teeth engage the plurality of slant-cut teeth to cause the plurality of slant-cut teeth to separate from the plurality of notches.

6. A drug delivery device as in claim 5, wherein, with return of the second shaft to being spaced from the first shaft, the plurality of slant-cut teeth are incrementally rotated and urged into engagement with the plurality of notches.

7. A drug delivery device as in claim 4, wherein the carrier includes a plurality of ramped surfaces defined on the inner surface thereof, the ramped surfaces being located among the plurality notches.

8. A drug delivery device for delivering drug from a plurality of drug cartridges to a patient, each of the drug cartridges including an elongated body having a first end sealed with a septum and a second open end, and, a stopper located in the body, wherein, in an initial state, each of the drug cartridges includes at least one drug contained in the body between the stopper and the septum thereof, the drug delivery device comprising: a cylindrical cassette configured to accommodate the plurality of drug cartridges; a plurality of cannulas positioned to simultaneously pierce the septa of the plurality of drug cartridges; a plurality of fluidic channels individually connected to the plurality of cannulas, the plurality of fluidic channels converging to a common outlet for delivery to the patient; a reversibly advanceable plunger; an indexing drive motor; a spur gear wheel coupled to the indexing drive motor; and, a toothed gear wheel coupled to the cassette, and in engagement with the spur gear wheel, wherein, with rotation of the spur gear wheel by the indexing drive motor, the toothed gear wheel is caused to rotate along with the cassette to align the plurality of drug cartridges individually with the plunger, the plunger being advanceable to urge the stopper of the aligned drug cartridge towards the septum of the aligned drug cartridge to cause the at least one drug contained in the body of the aligned drug cartridge to be expelled through the cannula piercing the septum of the aligned drug cartridge.

9. A drug delivery device as in claim 8, wherein, the indexing drive motor is reversible.

10. A drug delivery device as in claim 8, wherein, one or more apertures are formed in the toothed gear wheel, and, wherein the plunger accesses the aligned drug cartridge through the one or more apertures.

11. A drug delivery device as in claim 1, wherein the indexer including: a first shaft coupled to the cassette so as to be rotatable therewith; and, a second shaft coaxially aligned with, and normally biased to be spaced from, the first shaft, wherein, the second shaft is axially shiftable to engage the first shaft, and, wherein, the first and second shafts include cooperating elements which cause incremental rotation of the first shaft, relative to the second shaft, upon the second shaft engaging the first shaft.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0033] FIG. 1—view of a standard 1.5 mL cartridge

[0034] FIG. 2—exploded view of the Cassette

[0035] FIG. 3—a complete Ready-for-Use (RTU) Cassette

[0036] FIG. 4—Manifold top and transparent view

[0037] FIG. 5—view of cassette with manifold top attached

[0038] FIG. 6—Belt worn Drive Unit

[0039] FIG. 7—View of Drive Unit UI and outer features

[0040] FIG. 8—Cassette door button with interlock

[0041] FIG. 9—Cassette revolving mechanism within drive unit

[0042] FIG. 10—Cassette revolving mechanism components

[0043] FIG. 11—Revolving mechanism operation

[0044] FIG. 12—Cross section view of Drive Unit components

[0045] FIG. 13—Plunger rod expelling cartridge contents

[0046] FIGS. 14-17—Alternate Drive Unit configuration

DETAILED DESCRIPTION

[0047] With reference to the Figures, drug combinations will be delivered and configured through the utilization of a disposable cassette 10, which contains an arrangement of liquid drug filled cartridges 1 for sequential injection. As known in the art, one or more of the cartridges may be dry/wet cartridges having separated dry and wet components allowing for solubilized, or other powder form drug, to be reconstituted by a diluent, within the cartridge (e.g., under movement of the stopper 3). As shown in FIG. 1, cartridges 1 are cylindrical glass tubes with one end being formed to accommodate a crimped septum seal 2. Once the septum seal 2 is crimped onto the cartridge 1, the cartridge 1 is filled with liquid drug product and a stopper 3 is inserted into the second open end to seal its contents. In order to dispense the fluid within the cartridge 1, a cannula 13, must first pierce the septum 2 to access the drug fluid chamber 4. With the fluidic pathway open, a force is applied against the stopper 3 compressing the fluid held inside the cartridge 1 pushing it out from the cartridge 1 through the fluid pathway of the cannula 13 transecting the septum 2.

[0048] As shown in FIG. 2, the cassette 10 is used to house and load a preconfigured arrangement of cartridges 1 into the drive unit 20 for delivery to the patient. The cassette 10 consists of a main body housing 5, with holding chambers 7 for multiple cartridges 1 positioned radially around its lateral axis, and, a housing top 6, which closes over the cartridges 1 held in the main body housing 5 capturing them within the main body housing 5. Cutouts on the bottom of the main body housing 8 under each cartridge 1 allow physical access to the stoppers 3 within cartridges 1, while cutouts 9 in the housing top 6 allow open access to the cartridge septa 2 shown in FIG. 3. The cassette 10 is cylindrical in shape and is depicted with a flat 11 on its outer surface which is used to control its orientation when loaded into the drive unit 20. This unique shape is used as a keying feature and can take the form of different shapes or features in other embodiments. The cassette 10 depicted in the provided figures, demonstrates the use of seven discrete cartridges 1; if fewer cartridges are needed, less could be assembled into the cassette 10 leaving empty holding chambers 7. In embodiments where more cartridges would be needed the cassette 10 could be designed to hold additional cartridges without limit. An RFID label or equivalent technology, containing drug content and order information could be attached to the main body housing 5 to communicate with the drive unit 20 prior to delivery to ensure that an authentic and correct cassette 10 is being used.

[0049] Illustrated in FIG. 4, the cassette manifold top 12, which is a body having an inner cavity negative to that of the cassette-housing top 6, is designed to be installed over the cassette housing top 6, over the cartridge septa 2, and to permanently lock to the cassette 10 body. Shown in FIG. 4, within the manifold top 12 positioned above each cartridge 1 is a sharpened cannula 13, which connects to a fluidic channel 14 within the manifold top 12, which all converge to a common output 15 at the axis of the manifold top 12. This common output 15 leads to an infusion set 16 with a needle 17 that is to be inserted into a patient's injection site on the abdomen. When the manifold top 12 is installed onto the loaded cassette 10 (FIG. 5) each cannula 13 pierces its respective septum 2 and creates a fluid path from all cartridges 1 in the cassette 10 to the infusion set 16. In embodiments, check valves could be installed inline of each cannula 13 in order to remedy back flushing into other cartridges 1 during injections. During the manufacturing process, the cannula 13 with the manifold top 12 would be hermetically sealed and the entire part with infusion set 16 would undergo a terminal sterilization process for example by use of gamma irradiation or ethylene oxide (EO).

[0050] As the drug product is held within the cassette 10, it is delivered to the patient by means of an electro-mechanical belt worn drive unit 20. As shown in FIG. 6, the drive unit 20 is attached to the patient by means of a belt or body strap 18; the cassette 10 is then loaded into the drive unit 20 with the infusion set 16 freely exiting from the drive unit 20. The infusion set 16 terminates with a 25 G or similar needle 17, which is inserted into the patient's abdominal injection site.

[0051] An overview of the drive unit's 20 outer features and controls are depicted in FIG. 7. On the front face of the drive unit 20 exists the cassette door 19 which is spring biased to automatically open and is used to cover the cassette receptacle drum 28 within the drive unit 20. The cassette door 19 has a cutout 21 to allow the infusion set 16 of the cassette 10 to pass through the cassette door 19 once it is closed. Atop the drive unit 20 exists a mechanical button 22, which is pressed by the user to unlatch the cassette door 19 on the front face of the device to allow it to open. To prevent users from opening the cassette door 19 during operation, the cassette door button 22 can be disabled internally via mechanical interlock 27 by the device (FIG. 8). Additionally atop the drive unit exists a simple user interface (FIG. 7) consisting of a power button 25, a start/pause button 23, and a series of progress LEDs 24. The power button 25 is pressed by the user to energize or turn off the device, while the start/pause button 23 is pressed by the user to begin or pause the infusion process. The number of LEDs 24 present on the UI is representative of the number of cartridges 1 loaded into the device. As the device progresses through the infusion process, the LEDs 24 will light up to signify the cartridge 1 has finished its infusion. These controls and indicators on the top lateral face are currently contained upon a PCB mounted behind the drive unit's 20 outer shell. In embodiments these controls could be replaced with a touch display or controlled remotely through a technology such as Bluetooth. In embodiments the individual PCB mounted LEDs may be replaced by a single organic LED (oLED) display. On the rear face of the device is a USB C connector 26, which is used as a receptacle to connect a charger to recharge the device's internal battery 39.

[0052] The cassette 10 is loaded into the cassette drum 28, which is shaped to accept the cassette's 10 outer shape in order to control the orientation of the cassette 10 when loaded into the drive unit 20 (FIG. 9). In the center axis of the cassette drum 28 is a spring-loaded retainer 30 which inserts into the center axis of the cassette 10. When the cassette 10 is pressed into the mechanism spring loaded tabs expand out from the retainer 30, capturing the cassette 10, locking it by its lateral axis within the cassette drum 28. The cassette drum 28 and retainer 30 are attached to the rotating end of the revolver mechanism 29. In embodiments, an RFID transmitter/receiver could be placed near the cassette drum 28 in order to identify and communicate with the loaded cassette 10.

[0053] The revolver mechanism 29, also referable to as an indexer, is configured to incrementally rotate the cassette 28, particularly to individually align the cartridge 1 with plunger rod 42.

[0054] As shown in FIG. 10, the revolver mechanism 29 is comprised of a cylindrical carrier 31 which has splines 32 and notches 33 radially cut into its inner walls. Extending into the carrier 31 is a driving shaft 34, which terminates within the carrier 31. This terminal end of the driving shaft 34 is hollow with an edge shaped into teeth 36. The outer surface of the driving shaft 34 within the carrier 31 is splined 35 to interface with the splines 32 of the carrier 31 allowing the driving shaft 34 to only move vertically within the carrier 31. The driving shaft 34 is spring biased to push away from the carrier 31. The cassette shaft 37 has the cassette drum 28 and retaining mechanism 30 at one end with the cassette shaft 37 terminating within the carrier 31. This terminal end of the cassette shaft 37 ending within the carrier 31 has a ring of slant-cut teeth 38 set around the shaft that interface with the notches 33 within the carrier 31, the tip is shaped to protrude into the hollowed end of the driving shaft 34. The cassette shaft 37 is able to rotate within the carrier 31 and is spring biased towards the carrier 31. Demonstrated in FIG. 11, with the slant-cut teeth 38 of the cassette shaft 37 interfaced within the notches 33 of the carrier 31, an external force overcomes the spring bias of the driving shaft 34, pushing it into the carrier 31 making contact with the cassette shaft 37. The teeth 36 at the end of the driving shaft 34 push the cassette shaft 37 up from the carrier 31 so that the slant-cut teeth 38 of the cassette shaft 37 clear the carrier notches 33. The teeth 36 of the driving shaft 34 then act as a ramp to guide the slant-cut teeth 38 of the cassette shaft 37 into the next notch 33 of the carrier 31. As the driving shaft 34 retracts back to its starting position, the spring bias of the cassette shaft 37 pushes the slant-cut teeth 38 into the proceeding notch 33 of the carrier 31, thus rotating the cassette shaft 37, and subsequently the attached cassette 10 by one notch. The number and geometry of slant-cut teeth 38 on the driving shaft 37, and carrier notches 33, control the resolution of indexing steps and ensure that the cartridges 1 within the cassette 10 are aligned axially with the plunger rod 42 of the drive unit 20.

[0055] In alternative embodiments, as shown in FIGS. 14-17, alternative means of rotating and aligning the cassette 10 can be considered, e.g., a separate indexing drive motor 45 with a spur gear wheel 46 engaging with a toothed gear wheel 47 fabricated integrally on the rear of the retainer 30. With rotation of the spur gear wheel 46 by the drive motor 45, the gear wheel 47 is caused to rotate, along with the cassette 10. The drive motor 45 may be reversible allowing for bi-directional rotational adjustment of the cassette 10. The gear wheel 47 is provided with one or more apertures 48 through which the plunger rod 42 may pass to access an aligned cartridge 1. To dispense drug, the one or more apertures 48 are aligned with the plunger rod 42 in axial alignment with the aligned cartridge 1. Further arrangements are possible, such as ratchet and pawl type mechanisms.

[0056] Ramped surfaces 44 may be formed on the inner wall of the carrier 31, between the notches 33, to direct the slant-cut teeth 38 into the next notches 38 upon rotation. Preferably, the ramped surfaces 44 are ramped downwardly in the desired direction of rotation.

[0057] Internal components of the drive unit 20 are shown in FIG. 12. The main components of the infusion drive system are a battery 39, encoder motor 40, drivetrain 41, and plunger rod 42. During an infusion the encoder motor 40 is energized and will turn the drivetrain 41 to rotate the screw drive 43 to extend the plunger rod 42 forward from its home position and into the cassette drum 28. An encoder motor 40 and custom firmware are used in order to track the position of the plunger rod 42. The firmware also has the capability of monitoring the current of the encoder motor 40, which is directly correlated to the force that is being exerted by the plunger rod 42. As the plunger rod 42 enters the cassette drum 28 it passes through the cassette's main housing 5 via the plunger cutouts 8 under each cartridge 1. The revolver mechanism 29 ensures that the plunger rod 42 will be axially aligned with the cartridge 10. Upon further travel, the plunger rod 42 then enters into the cartridge 1 making contact with the cartridge stopper 3. The plunger rod 42 will continue to extend forward and will begin to drive the cartridge stopper 3 into the cartridge 1 (FIG. 13) expelling its contents into the cannula 13 piercing its septum 2, into the cassette top manifold 12, out into the infusion set 16, and into the patient. Once the contents of the cartridge 1 have been fully expelled, the encoder motor 40 will then be reversed to retract the plunger rod 42 back to its home position. Upon reaching home position, the plunger rod 42 will be retracted further past home position to interface with the driving shaft 34 of the revolver mechanism 29. Upon further retraction of the plunger rod 42 the driving shaft 34 of the revolver mechanism 29 is driven into the carrier 31 resulting in the indexing of cassette drum 28 by one notch, or cartridge position 1. Once the revolver index has completed the plunger rod 42 resets to its home position to repeat the process for the proceeding cartridge 1 in the cassette 10. In embodiments, the rigid plunger rod 42 could be replaced with a flexible or telescoping plunger rod. Likewise, the means of driving the plunger rod 42 could be substituted with a linear actuator, pneumatic, magnetic, or spring based system.

[0058] As will be appreciated by those skilled in the art, the subject invention may be used to dose the cartridges 1 in various sequences, including variations in full and partial dosing of the cartridges 1. For example, the cassette 10 may be caused to rotate to allow for delivery in sequential order of the cartridges 1 or one or more of the cartridges 1 may be skipped with additional rotation, allowing for later delivery. Also, the plunger rod 42 may be used to cause partial dosing of one or more of the cartridges 1, allowing for return to permit further delivery from the same cartridge 1, thus allowing for multiple dosings from one or more of the cartridges 1, in an established pattern. The flexibility in operation allows for multiple drugs to be delivered in different amounts and in different sequences, allowing for different combinations being delivered at different instances.

[0059] In one embodiment, any of the combinatorial drug delivery devices disclosed herein is able to deliver two or more drugs for the benefit of the patient suffering from any of a wide range of diseases or conditions, e.g., cancer, autoimmune disorder, inflammatory disorder, cardiovascular disease or fibrotic disorder. In one embodiment, one or more of the cartridges 1 may contain a single drug. In one embodiment, one or more of the cartridges 1 may contain two or more co-formulated drugs. In one embodiment, one or more of the cartridges 1 may contain a drug in solid form (such as a tablet, capsule, powder, lyophilized, spray dried), which can be reconstituted with flow of a diluent therein to form a liquid drug.

[0060] In one embodiment, one or more of the drugs of any of the combinatorial drug delivery devices disclosed herein is an immune checkpoint inhibitor. In certain embodiments, the immune checkpoint inhibitor is 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, a Indoleamine 2,3-dioxygenase (“IDO1”) antagonist, a stimulator of interferon genes (“STING”) antagonist, a GARP antagonist, a CD40 antagonist, Adenosine A2A receptor (“A2aR”) antagonist, a CEACAM1 (CD66a) antagonist, a CEA antagonist, a CD47 antagonist, a Receptor Related Immunoglobulin Domain Containing Protein (“PVRIG”) antagonist, a tryptophan 2,3-dioxygenase (“TDO”) antagonist, a V-domain Ig suppressor of T cell activation (“VISTA”) antagonist, or a Killer-cell Immunoglobulin-like Receptor (“KIR”) antagonist.

[0061] In one embodiment, the PD-1 pathway inhibitor is an anti-PD-1 antibody or 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.

[0062] In one embodiment, the PD-1 pathway inhibitor is an anti-PD-L1 antibody or antigen binding fragment thereof. In certain embodiments, the anti-PD-L1 antibody is atezolizumab (TECENTRIQ; RG7446; MPDL3280A; R05541267), durvalumab (MEDI4736), BMS-936559, avelumab (bavencio), LY3300054, CX-072 (Proclaim-CX-072), FAZ053, KN035, or MDX-1105.

[0063] 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 MiHA-loaded PD-L1/L2-silenced dendritic cell vaccine. In other embodiments, the cell based therapy is an anti-programmed cell death protein 1 antibody expressing pluripotent killer T lymphocyte, an autologous PD-1-targeted chimeric switch receptor-modified T lymphocyte, or a PD-1 knockout autologous T lymphocyte.

[0064] In one embodiment, the PD-1 pathway inhibitor is an anti-PD-L2 antibody or antigen binding fragment thereof. In another embodiment, the anti-PD-L2 antibody is rHIgM12B7.

[0065] 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 PD-1 extracellular domain. In other embodiments, the soluble PD-1 polypeptide comprises a ligand binding fragment of the PD-1 extracellular domain. In another embodiment, the soluble PD-1 polypeptide further comprises an Fc domain.

[0066] 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 antigen binding fragment thereof In some embodiments, the anti-CTLA-4 antibody is ipilimumab (YERVOY), tremelimumab (ticilimumab; CP-675,206), AGEN-1884, or ATOR-1015. In one embodiment, any of the combinatorial drug delivery devices disclosed herein includes a CTLA-4 antagonist, e.g., ipilimumab (YERVOY), and a PD-1 pathway inhibitor, e.g., nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA).

[0067] In one embodiment, the immune checkpoint inhibitor is an antagonist of LAG3. In certain embodiments, the LAG3 antagonist is an anti-LAG3 antibody or 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 of the combinatorial drug delivery devices disclosed herein includes a LAG3 antagonist, e.g., relatlimab or MK-4280, and a PD-1 pathway inhibitor, e.g., nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA). In one embodiment, any of the combinatorial drug delivery devices disclosed herein includes a LAG3 antagonist, e.g., relatlimab or MK-4280, and a CTLA-4 antagonist, e.g., ipilimumab (YERVOY). In one embodiment, any of the combinatorial drug delivery devices disclosed herein includes a LAG3 antagonist, e.g., relatlimab or MK-4280, a CTLA-4 antagonist, e.g., ipilimumab (YERVOY), and a PD-1 pathway inhibitor, e.g., nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA).

[0068] In one embodiment, the immune checkpoint inhibitor is a KIR antagonist. In certain embodiments, the KIR antagonist is an anti-KIR antibody or antigen binding fragment thereof. In some embodiments, the anti-KIR antibody is lirilumab (1-7F9, BMS-986015, IPH 2101) or IPH4102.

[0069] In one embodiment, the immune checkpoint inhibitor is TIGIT antagonist. In one embodiment, the TIGIT antagonist is an anti-TIGIT antibody or antigen binding fragment thereof. In certain embodiments, the anti-TIGIT antibody is BMS-986207, AB 154, COM902 (CGEN-15137), or OMP-313M32.

[0070] In one embodiment, the immune checkpoint inhibitor is Tim-3 antagonist. In certain embodiments, the Tim-3 antagonist is an anti-Tim-3 antibody or antigen binding fragment thereof. In some embodiments, the anti-Tim-3 antibody is TSR-022 or LY3321367.

[0071] In one embodiment, the immune checkpoint inhibitor is an IDO1 antagonist. In another embodiment, the IDO1 antagonist is indoximod (NLG8189; 1-methyl-.sub.D-TRP), epacadostat (INCB-024360, INCB-24360), KHK2455, PF-06840003, navoximod (RG6078, GDC-0919, NLG919), BMS-986205 (F001287), or pyrrolidine-2,5-dione derivatives.

[0072] In one embodiment, the immune checkpoint inhibitor is a STING antagonist. In certain embodiments, the STING antagonist is 2′ or 3′-mono-fluoro substituted cyclic-di-nucleotides; 2′3′-di-fluoro substituted mixed linkage 2′,5′-3′,5′ cyclic-di-nucleotides; 2′-fluoro substituted, bis-3′,5′ cyclic-di-nucleotides; 2′,2″-diF-Rp,Rp,bis-3′,5′ cyclic-di-nucleotides; or fluorinated cyclic-di-nucleotides.

[0073] In one embodiment, the immune checkpoint inhibitor is CD20 antagonist. In some embodiments, the CD20 antagonist is an anti-CD20 antibody or antigen binding fragment thereof. In one embodiment, the anti-CD20 antibody is rituximab (RITUXAN; IDEC-102; IDEC-C2B8), ABP 798, ofatumumab, or obinutuzumab.

[0074] In one embodiment, the immune checkpoint inhibitor is CD80 antagonist. In certain embodiments, the CD80 antagonist is an anti-CD80 antibody or antigen binding fragment thereof. In one embodiment, the anti-CD80 antibody is galiximab or AV 1142742.

[0075] In one embodiment, the immune checkpoint inhibitor is a GARP antagonist. In some embodiments, the GARP antagonist is an anti-GARP antibody or antigen binding fragment thereof. In certain embodiments, the anti-GARP antibody is ARGX-115.

[0076] In one embodiment, the immune checkpoint inhibitor is a CD40 antagonist. In certain embodiments, the CD40 antagonist is an anti-CD40 antibody for antigen binding fragment thereof. In some embodiments, the anti-CD40 antibody is BMS3h-56, lucatumumab (HCD122 and CHIR-12.12), CHIR-5.9, or dacetuzumab (huS2C6, PRO 64553, RG 3636, SGN 14, SGN-40). In another embodiment, the CD40 antagonist is a soluble CD40 ligand (CD40L). In one embodiment, the soluble CD40 ligand is a fusion polypeptide. In one embodiment, the soluble CD40 ligand is a CD40L/FC2 or a monomeric CD40-L.

[0077] 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.

[0078] In one embodiment, the immune checkpoint inhibitor is a CEACAM1 antagonist. In some embodiments, the CEACAM1 antagonist is an anti-CEACAM1 antibody or antigen binding fragment thereof. In one embodiment, the anti-CEACAM1 antibody is CM-24 (MK-6018).

[0079] In one embodiment, the immune checkpoint inhibitor is a CEA antagonist. In one embodiment, the CEA antagonist is an anti-CEA antibody or antigen binding fragment thereof. In certain embodiments, the anti-CEA antibody is cergutuzumab amunaleukin (RG7813, RO-6895882) or RG7802 (RO6958688).

[0080] In one embodiment, the immune checkpoint inhibitor is a CD47 antagonist. In some embodiments, the CD47 antagonist is an anti-CD47 antibody or 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.

[0081] In one embodiment, the immune checkpoint inhibitor is a PVRIG antagonist. In certain embodiments, the PVRIG antagonist is an anti-PVRIG antibody or antigen binding fragment thereof. In one embodiment, the anti-PVRIG antibody is COM701 (CGEN-15029).

[0082] In one embodiment, the immune checkpoint inhibitor is a TDO antagonist. In one embodiment, the TDO antagonist is a 4-(indol-3-yl)-pyrazole derivative, a 3-indol substituted derivative, or a 3-(indol-3-yl)-pyridine derivative. In another embodiment, the immune checkpoint inhibitor is a dual IDO and TDO antagonist. In one embodiment, the dual IDO and TDO antagonist is a small molecule.

[0083] In one embodiment, the immune checkpoint inhibitor is a VISTA antagonist. In some embodiments, the VISTA antagonist is CA-170 or JNJ-61610588.

[0084] In one embodiment, one or more of the drugs of any of the combinatorial drug delivery devices disclosed herein is an immune checkpoint enhancer or stimulator.

[0085] 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.

[0086] 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 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 (iC9-GD2-CD28-OX40-expressing T lymphocytes).

[0087] 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 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 (AVREND®).

[0088] 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 antigen binding fragment thereof. 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 anti-CTLA4 mAb RNA/GITRL RNA-transfected autologous dendritic cell vaccine or a GITRL RNA-transfected autologous dendritic cell vaccine.

[0089] In one embodiment, the immune checkpoint enhancer or stimulator a 4-1BB agonist. In some embodiments, the 4-1BB agonist is an anti-4-1BB antibody or antigen binding fragment thereof. In one embodiment, the anti-4-1BB antibody is urelumab or PF-05082566.

[0090] In one embodiment, the immune checkpoint enhancer or stimulator is a CD80 agonist or a CD86 agonist. In some embodiments, the CD80 agonist or the CD86 agonist is a soluble CD80 or CD86 ligand (CTLA-4). In certain embodiments, the soluble CD80 or CD86 ligand is a fusion polypeptide. In one embodiment, the CD80 or CD86 ligand is CTLA4-Ig (CTLA4-IgG4m, RG2077, or RG1046) or abatacept (ORENCIA, BMS-188667). In other embodiments, the CD80 agonist or the CD86 agonist is a cell based therapy. In one embodiment, the cell based therapy is MGN1601 (an allogeneic renal cell carcinoma vaccine).

[0091] 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 antigen binding fragment thereof. In certain embodiments, the anti-CD28 antibody is TGN1412.

[0092] In one embodiment, the CD28 agonist is a cell based therapy. In certain embodiments, the cell based therapy is JCAR015 (anti-CD19-CD28-zeta modified CAR CD3+ T lymphocyte); CD28CAR/CD137CAR-expressing T lymphocyte; allogeneic CD4+ memory Th1-like T cells/microparticle-bound anti-CD3/anti-CD28; anti-CD19/CD28/CD3zeta CAR gammaretroviral vector-transduced autologous T lymphocytes KTE-C19; anti-CEA IgCD28TCR-transduced autologous T lymphocytes; anti-EGFRvIII CAR-transduced allogeneic T lymphocytes; autologous CD123CAR-CD28-CD3zeta-EGFRt-expressing T lymphocytes; autologous CD171-specific CAR-CD28 zeta-4-1-BB-EGFRt-expressing T lymphocytes; autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T cells; autologous PD-1-targeted chimeric switch receptor-modified T lymphocytes (chimera with CD28); CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T lymphocytes; CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T lymphocytes; CD19CAR-CD28zeta-4-1BB-expressing allogeneic T lymphocytes; CD19CAR-CD3zeta-4-1BB-CD28-expressing autologous T lymphocytes; CD28CAR/CD137CAR-expressing T lymphocytes; CD3/CD28 costimulated vaccine-primed autologous T lymphocytes; or iC9-GD2-CD28-OX40-expressing T lymphocytes.

[0093] 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 antigen binding fragment thereof. In one embodiment, the anti-CD27 antibody is varlilumab (CDX-1127).

[0094] 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 antigen binding fragment thereof. In one embodiment, the anti-CD70 antibody is ARGX-110.

[0095] 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 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.

[0096] In one embodiment, one or more of the drugs of any of the combinatorial drug delivery devices disclosed herein is an anti-CD73 antibody or antigen binding fragment thereof. In certain embodiments, the anti-CD73 antibody is MEDI9447.

[0097] In one embodiment, one or more of the drugs of any of the combinatorial drug delivery devices disclosed herein is a TLR9 agonist. In one embodiment, the TLR9 agonist is agatolimod sodium.

[0098] In one embodiment, one or more of the drugs of any of the combinatorial drug delivery devices disclosed herein is a cytokine. In certain embodiments, the cytokine is a chemokine, an interferon, an interleukin, lymphokine, or a member of the tumor necrosis factor family. In some embodiments, the cytokine is IL-2, IL-15, or interferon-gamma.

[0099] In one embodiment, one or more of the drugs of any of the combinatorial drug delivery devices 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-beta-2; autologous HPV-16/18 E6/E7-specific TGF-beta-resistant T lymphocytes; or TGF-beta-resistant LMP-specific cytotoxic T-lymphocytes.

[0100] In one embodiment, one or more of the drugs of any of the combinatorial drug delivery devices disclosed herein is an iNOS antagonist. In some embodiments, the iNOS antagonist is N-Acetyle-cysteine (NAC), aminoguanidine, L-nitroarginine methyl ester, or S,S-1,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea).

[0101] In one embodiment, one or more of the drugs of any of the combinatorial drug delivery devices disclosed herein is a SHP-1 antagonist.

[0102] In one embodiment, one or more of the drugs of any of the combinatorial drug delivery devices disclosed herein is a colony stimulating factor 1 receptor (“CSF1R”) antagonist. In certain embodiments, the CSF1R antagonist is an anti-CSF1R antibody or antigen binding fragment thereof. In some embodiments, the anti-CSF1R antibody is emactuzumab.

[0103] In one embodiment, one or more of the drugs of any of the combinatorial drug delivery devices disclosed herein is an agonist of a TNF family member. In some embodiments, the agonist of the TNF family member is ATOR 1016, ABBV-621, or Adalimumab.

[0104] In one embodiment, one or more of the drugs of any of the combinatorial drug delivery devices disclosed herein is an Interleukin-2 (IL-2), such as aldesleukin. Preferably, the IL-2 or conjugated IL-2 (e.g., pegylated) has been modified to selectively activate T-effector cells over T-regulatory cells (“T-eff IL-2”), such as bempegaldesleukin. In one embodiment, any of the combinatorial drug delivery devices disclosed herein includes a modified IL-2, such as bempegaldesleukin, which selectively activates T-effector cells over T-regulatory cells, and a PD-1 pathway inhibitor, e.g., nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA). In one embodiment, any of the combinatorial drug delivery devices disclosed herein includes a modified IL-2, such as bempegaldesleukin, which selectively activates T-effector cells over T-regulatory cells, and a LAG3 antagonist, e.g., relatlimab or MK-4280. In one embodiment, any of the combinatorial drug delivery devices disclosed herein includes a modified IL-2, such as bempegaldesleukin, which selectively activates T-effector cells over T-regulatory cells, and a PD-1 pathway inhibitor, e.g., nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA), and a LAG3 antagonist, e.g., relatlimab or MK-4280. In one embodiment, any of the combinatorial drug delivery devices disclosed herein includes a modified IL-2, such as bempegaldesleukin, which selectively activates T-effector cells over T-regulatory cells and a CTLA-4 antagonist, e.g., ipilimumab (YERVOY). In one embodiment, any of the combinatorial drug delivery devices disclosed herein includes a modified IL-2, such as bempegaldesleukin, which selectively activates T-effector cells over T-regulatory cells, a PD-1 pathway inhibitor, e.g., nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA), and a CTLA-4 antagonist, e.g., ipilimumab (YERVOY). In one embodiment, any of the combinatorial drug delivery devices disclosed herein includes a modified IL-2, such as bempegaldesleukin, which selectively activates T-effector cells over T-regulatory cells, a CTLA-4 antagonist, e.g., ipilimumab (YERVOY), and a LAG3 antagonist, e.g., relatlimab or MK-4280. In one embodiment, any of the combinatorial drug delivery devices disclosed herein includes a modified IL-2, such as bempegaldesleukin, which selectively activates T-effector cells over T-regulatory cells, a PD-1 pathway inhibitor, e.g., nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA), a CTLA-4 antagonist, e.g., ipilimumab (YERVOY), and a LAG3 antagonist, e.g., relatlimab or MK-4280.

[0105] In one embodiment, one or more of the drugs of any of the combinatorial drug delivery devices disclosed herein is a CD160 (NK1) agonist. In certain embodiments, the CD160 (NK1) agonist is an anti-CD160 antibody or antigen binding fragment thereof. In one embodiment, the anti-CD160 antibody is BY55.

[0106] In one embodiment, the one or more of the cartridges 1 may contain a soluble CTLA-4 polypeptide, which can be useful for treating, for instance, 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 of the cartridges 1 of a combinatorial drug delivery device as described herein include a soluble CTLA-4 polypeptide, e.g., abatacept (ORENCIA) and a Bruton's tyrosine kinase inhibitor, e.g., branebrutinib. In certain embodiments, one or more of the cartridges 1 of a combinatorial drug delivery device as described herein include a soluble CTLA-4 polypeptide, e.g., abatacept (ORENCIA) and a tyrosine kinase-2 inhibitor, e.g., BMS-986165. In certain embodiments, one or more of the cartridges 1 of a combinatorial drug delivery device as described herein include a soluble CTLA-4 polypeptide, e.g., abatacept (ORENCIA) and an Interleukin-2 (IL-2) or “T-reg IL-2”, which selectively activates T-regulatory cells as opposed to T-effector cells, e.g., BMS-986326 and NKTR-358.