Circumferentially adjustable multi-cartridge drug delivery device with cross elements suitable for subcutaneous injection for combination drugs

Abstract

In one aspect of the present invention, a drug delivery device is provided for delivering drugs to a patient from a plurality of drug cartridges. Each drug cartridge includes an elongate body having a first end sealed by a septum and an open second end, and a stopper disposed within the body. Initially, each drug cartridge contains at least one drug within the body between the stopper and the septum. The drug delivery device includes a cylindrical cassette configured to accommodate the plurality of drug cartridges, a reversibly advanceable plunger, a first shaft having a cross element attached thereto, and a reversibly rotatable drive member attached to the second shaft for rotation with the second shaft about a rotary drive axis. The first shaft is coupled to the cassette so that the cassette rotates with the rotation of the cross element to individually align multiple drug cartridges with the plunger, and the plunger is advanceable to force a stopper toward a septum in an aligned drug cartridge. The cross element has a plurality of blades separated from one another by slots, each blade extending radially outward from the center of the cross element to an exposed free end, the free ends of the plurality of blades collectively defining a discontinuous outer edge of the cross element that surrounds the first shaft. The drive member has a first end face oriented in a direction parallel to the rotary drive shaft, a drive pin protruding from the first end face along a first direction parallel to the rotary drive shaft, a second end face offset in the first direction from the first end face, and a side wall formed on the outer periphery of the drive member at a height between the first and second end faces. The drive member is positioned so that the side wall faces the outer edge of the cross element. Rotation of the drive member about the rotary drive shaft drives the drive pin through an arc, and as the drive pin passes through a first portion of the arc, the drive pin is received in a first slot of the cross element. As the drive pin passes through a second portion of the arc, the drive pin presses against a first blade of the plurality of blades adjacent to the first slot, generating a moment about the first shaft to rotate the cassette.As the drive pin passes through the third portion of the arc, it ceases to press against the first blade and exits the first slot. Advantageously, the present invention provides an arrangement for reversibly adjusting the medication cartridge in various fixed increments.

Description

[Technical Field]

[0001] The field of the present invention is the subcutaneous administration of liquid drugs. More specifically, the present invention relates to the subcutaneous administration of two or more liquid drugs in a fixed weight ratio. [Background technology]

[0002] For various reasons, many drugs must be administered parenterally. For example, biotechnology-derived biological drugs (biopharmaceuticals) are therapeutic proteins that cannot be administered orally because they would be destroyed in the digestive system and lose their effectiveness. Therefore, such biological drugs are usually administered by routes that bypass the digestive system, most commonly intravenously and subcutaneously.

[0003] Recent advances in medicine, particularly in cancer treatment, have demonstrated that synergistic combinations of two or more drugs can provide beneficial therapeutic effects.

[0004] For example, recent clinical studies have demonstrated that the combination of anti-PD-1 and CTLA4 immune checkpoint inhibitors can produce beneficial synergistic effects in some tumor types, resulting in better clinical outcomes than either drug administered alone. These immune checkpoint inhibitors are often biotechnology-derived immunoglobulin-type monoclonal antibodies or their fragments. In some cases, it may be beneficial to combine these biologics with conventional chemotherapeutic agents (e.g., cytotoxic drugs).

[0005] Parenteral drug combinations present several challenges, and various approaches have been attempted to overcome these challenges. These challenges include increased dosing complexity, increased risk of dosing errors, and increased patient burden. Increased dosing complexity manifests itself in various ways depending on the method of drug combination and administration. For example, one approach to combining multiple therapeutic biologics is to co-formulate them into a fixed-ratio solution. The need to ensure a stable formulation that maintains the potency and quality of the combined drugs throughout the pharmaceutical supply chain creates formulation complexity. As those skilled in the art will appreciate, such formulations typically contain multiple excipients (e.g., buffers, pH adjusters, tonicity adjusters, stabilizers, etc.). The greater the number of drugs combined, the greater the formulation complexity. Related to formulation challenges is the challenge of developing analytical methods for such complex formulations (e.g., assays to assess the quality, efficacy, and potency of each drug in the mixture). A further limitation of fixed-ratio combinations is the loss of flexibility in the ratio of the drugs administered.

[0006] Compounding medications from single-dose formulations near the point of care (e.g., a compounding pharmacy) avoids formulation and analytical complexities and maintains dosing flexibility. In this case, a pharmacist or pharmacy technician follows a procedure for mixing individual medications using aseptic techniques under a compounding hood. Most commonly, this approach is currently applied to mixing medications in intravenous infusion bags, but in principle, it could also be applied to mixing medications in vials for subsequent subcutaneous injection. While this approach avoids formulation and analytical complexities, it leaves those complexities to the pharmacy. When used to prepare intravenous solutions, this approach can only be implemented near the point of care for patients attending infusion clinics. The benefit of flexibility in dosage and administration ratios gained through this approach carries the risk of medication errors in the pharmacy (e.g., using the wrong medication or mixing in the wrong ratio). While well-managed pharmacies have checks and controls in place to prevent such medication errors, this risk is another reason why this practice is limited to pharmacies near the point of care (e.g., hospitals). A final risk associated with dispensing in pharmacies is the risk of drug exposure and needlestick injuries due to the need for multiple drug transfers through a needle. This risk can be reduced by the use of dispensing machines in pharmacies, but such machines add an additional layer of complexity and expense.

[0007] Formulation and analytical complexities can be avoided by administering drugs separately (e.g., as separate intravenous infusions or subcutaneous injections). In some cases, this approach may be necessary for technical reasons (e.g., when a fixed ratio formulation is not consistently available). In the case of intravenous administration, this approach only slightly reduces procedural complexity for pharmacies that must manage multiple compounded infusions. Furthermore, this approach does not eliminate the risk of medication errors. In both intravenous and subcutaneous administration, patients must tolerate multiple infusions or injections, which increases their burden.

[0008] In some cases, safety reasons may prevent all drugs from being administered at once, for example, when excipient burdens are unacceptably high. For bacterial cell culture-derived biologics, residual bacterial endotoxin levels are controlled as low as possible during downstream processing, but multiple drugs may still not be administered simultaneously. Managing excipient and endotoxin burdens may require patients to stay hospitalized for several days or to visit the hospital for several days, further increasing the burden on patients.

[0009] In principle, drugs intended for coadministration could be provided individually in convenient prefilled devices for subcutaneous administration (e.g., prefilled syringes, autoinjectors, or on-body injectors) and self-administered by patients at locations away from the clinical setting. While this approach may reduce the need for patient hospitalization and multiple visits, it requires multiple injections, resulting in patient inconvenience and associated safety risks (e.g., injection site reactions). This approach also poses a significant risk of medication errors, as patients must be aware of the administration status of each drug in the combination. If the timing of administration of each drug is critical for safety or therapeutic reasons, such as endotoxin management, there is also a risk of medication errors due to incorrect timing of component drug administration. While the risk of medication errors can be mitigated to some extent by copackaging with clear instructions, it cannot be completely eliminated.

[0010] Currently, for the reasons stated above, in clinical settings, most parenterally administered compounded drugs are administered by the intravenous route.

[0011] For pharmaceutical companies that manufacture and sell drugs as combination therapies, this co-formulation approach creates new challenges and complexities in manufacturing and the supply chain. For pharmaceutical companies with product lines of individual drugs that are used in combination with each other, these complexities increase as the number of combinations offered increases.

[0012] Each new drug combination adds a stockkeeping unit (SKU) to finished goods inventory. Furthermore, each change in drug mix or strength adds even more SKUs. This rapid proliferation of SKUs is known in supply chain management as "combinatorial explosion." From an accounting perspective, these SKUs are counted as finished goods inventory. Work-in-process inventory (WIP) introduces additional complexity because individual active pharmaceutical ingredients (APIs) must be stored in bulk until dispensed. Subsequently, the bulk dispensed drug products must similarly be stored until filled into unit doses. Biologics, which are typically stored deep frozen, require multiple freeze-thaw cycles, resulting in the need for extensive refrigerated storage facilities and equipment.

[0013] In particular, when the drug in question is an expensive biological drug, the financial impact of combinatorial explosion and the resulting inventory buildup can be significant not only because of the working capital tied up in inventory, but also because of the expensive equipment required to store work-in-process and finished product inventories in refrigerated conditions.

[0014] The challenge of optimizing product blends among various combinations of SKUs in response to market demand creates additional challenges for supply chain planning and forecasting regarding blended drug combinations. Because bulk-stored active pharmaceutical ingredients (APIs) are distributed across a potentially large number of finished product SKUs, accurate demand forecasting is essential to minimize the risk of overstocking some SKUs and shortages (stock-outs) of others. For expensive biopharmaceuticals, the costs associated with forecasting errors can be significant. This problem is exacerbated because pharmaceuticals are perishable commodities, meaning that unsold inventory can only be stored for a limited period of time before being written off. Clearly, these forecasting challenges grow as the number of drugs used in a blend and the number of SKUs within a product line increase.

[0015] Taken together, for all the aforementioned reasons, there is a need for technologies that can address each of these challenges associated with administering combination therapies. An ideal technology would avoid the formulation and analytical complexities of fixed-ratio combination formulations, avoid combination explosion and inventory buildup in manufacturing and the supply chain, eliminate the risk of medication errors at the pharmacy and point of care (clinic or home), and minimize the patient burden associated with multiple infusions, injections, and administration timing constraints. An ideal technology would also maximize patient convenience by enabling flexible and convenient delivery of combination therapies, for example, in the home or other nonclinical settings. To maximize patient convenience, an ideal technology would enable subcutaneous administration, which is more suitable for nonclinical settings. An ideal technology would also anticipate medical advances, such as the development of more complex combination therapies. More complex combination therapies include three or more drugs and an active excipient such as a hyaluronidase enzyme (e.g., recombinant human hyaluronidase enzyme sold under the brand name ENHANZE™ by Halozyme Therapeutics, Inc., San Diego, California).

[0016] As a further example of medical advances, recent advances in immuno-oncology suggest that precise timing of administration of component drugs in a combination therapy may offer therapeutic benefits. For example, a combination therapy of "drug A" and "drug B," designed to target two biochemical targets "A" and "B," respectively, expressed by a specific tumor type, may be considered as follows: Recent developments suggest that tumor target expression has a temporal aspect, and that the timing of administration of each drug can affect that expression. For example, administration of drug A to bind to target A may stimulate or upregulate the expression of target B some time later (e.g., minutes, hours, or even days). In such cases, it may be optimal to administer drug B when the expression of target B has peaked. Such temporally separated administration may be optimal for reasons of safety (e.g., reducing the drug dosage required to achieve equivalent therapeutic effect), efficacy, or both.

[0017] Given the biological nature of these time-resolved effects, temporally separated administration may not be compatible with traditional clinical schedules and may require clinic visits for infusions on nontraditional schedules, potentially increasing both the clinical and patient burden of treatment. Therefore, to fully utilize these effects, subcutaneous administration in nonclinical settings is necessary to maximize flexibility in administration timing.

[0018] Therefore, the ideal technique described above, which allows subcutaneous injection, is also suitable for time-resolved administration in therapeutic combinations.

[0019] The present applicant has discovered that the above-described ideal technology requirements can be realized by implementing the combination principles described in the present applicant's co-pending applications, U.S. Provisional Patent Application No. 62 / 670266, International Patent Application No. PCT / US2019 / 031727, International Patent Application No. PCT / 2019 / 031762, and International Patent Application No. PCT / US2019 / 031791 (the entire contents of each of which are incorporated herein by reference), into a subcutaneous delivery device.

[0020] The present applicant has developed a drug delivery device for combination drugs with multiple, radially adjustable cartridges, as disclosed in U.S. Patent Application No. 17 / 771935 and International Patent Application No. PCT / 2020 / 059672 (the entire contents of each of which are incorporated herein by reference). This drug delivery device uses an indexer or gear wheel to rotate a cassette containing multiple drug cartridges. As the cartridges rotate, they are individually aligned with an advanceable plunger. The plunger is configured to eject the drug from the aligned cartridge. When an indexer is used, the limited reversible rotation limits rapid alignment of the drug cartridges to enable specific dosing sequences of multiple drug components. When a gear wheel is used, radially adjustable adjustment is possible in increments, but is limited by the size of the available gear teeth. Summary of the Invention

[0021] In one aspect of the present invention, a drug delivery device is provided for delivering drugs to a patient from multiple drug cartridges. Each drug cartridge includes an elongated body having a first end sealed with a septum and an open second end, and a stopper disposed within the body. In an initial state, each drug cartridge contains at least one drug contained within the body between the stopper and the septum. The drug delivery device includes a cylindrical cassette configured to accommodate multiple drug cartridges, a reversibly advanceable plunger, a first shaft to which a cross element is attached, and a reversibly rotatable drive member attached to the second shaft for rotation with the second shaft about a rotational drive axis. The first shaft is coupled to the cassette such that the cassette rotates with rotation of the cross element to individually align the multiple drug cartridges with the plunger. The plunger is advanceable to push the stopper toward the septum of an aligned drug cartridge. The cross element has a plurality of blades separated from one another by slots. Each blade generally extends radially outward from the center of the cross element to an exposed free end. The free ends of the blades collectively define a discontinuous outer edge of the cross element that surrounds the first shaft. The drive member has a first end face oriented parallel to the rotary drive shaft, a drive pin protruding from the first end face along a first direction parallel to the rotary drive shaft, a second end face offset from the first end face in the first direction, and a sidewall formed on the outer periphery of the drive member at a height between the first end face and the second end face. The drive member is oriented such that the sidewall is aligned opposite the outer edge of the cross element. Rotation of the drive member about the rotary drive shaft drives the drive pin to describe an arc.As the drive pin passes through (moves across) a first portion of the arc, it is received in a first of the slots in the cross element. As the drive pin passes through (moves across) a second portion of the arc, it presses against a first blade of the plurality of blades adjacent to the first slot, generating a moment about the first shaft to rotate the cassette. As the drive pin passes through (moves across) a third portion of the arc, it releases itself from pressing against the first blade and exits the first slot. The present invention has the advantage of providing an arrangement for reversibly adjusting a drug cartridge in various fixed increments.

[0022] Additionally, the exposed free end surface of the cross element can engage a sidewall surface of the rotary drive member, thereby allowing the rotary drive member to captively hold the cross element during indexing of the cassette, thereby preventing undesired rotation of the cassette.

[0023] These and other features of the present invention will be better understood with reference to the following detailed description and accompanying drawings. [Brief explanation of the drawings]

[0024] [Figure 1] 1 shows a drug delivery device according to the invention described herein. [Figure 2] 1 shows a drug delivery device according to the invention described herein. [Figure 3] 1 shows a drug delivery device according to the invention described herein. [Figure 4] 1 shows a drug delivery device according to the invention described herein. [Figure 5] 1 shows a drug delivery device according to the invention described herein. [Figure 6] 1 shows a drug delivery device according to the invention described herein. [Figure 7] 1 shows a drug delivery device according to the invention described herein. [Figure 8] 1 shows a drug delivery device according to the invention described herein. [Figure 9] 1 shows a drug delivery device according to the invention described herein. [Figure 10] 1 shows a drug delivery device according to the invention described herein. [Figure 11] 1 shows a drug delivery device according to the invention described herein. [Figure 12] 1 shows a drug delivery device according to the invention described herein. [Figure 13] 1 shows a drug delivery device according to the invention described herein. [Figure 14] 1 shows a drug delivery device according to the invention described herein. [Figure 15] 1 shows a drug delivery device according to the invention described herein. [Figure 16] 1 shows a drug delivery device according to the invention described herein. [Figure 17] 1 shows a drug delivery device according to the invention described herein. [Figure 18] 1 shows a drug delivery device according to the invention described herein. [Figure 19] 1 shows a drug delivery device according to the invention described herein. [Figure 20] 1 shows a drug delivery device according to the invention described herein. [Figure 21] 1 shows a drug delivery device according to the invention described herein. DETAILED DESCRIPTION OF THE INVENTION

[0025] As shown in each figure, a combination drug is delivered and configured using a disposable cassette 10. Within the cassette 10, multiple cartridges 1 filled with a liquid drug are arranged for continuous infusion. As is well known in the art, one or more cartridges may be dry / wet cartridges in which the dry and wet components are separated, allowing a solubilized or other powdered drug to be reconstituted within the cartridge by a diluent (e.g., under the movement of a stopper 3). As shown in FIG. 1 , the cartridge 1 is a cylindrical glass or polymer tube. One end (first end) of the cartridge 1 is configured to accommodate a (e.g., crimped) septum seal (hereinafter also referred to as "septum 2"). Once the septum 2 is secured to the cartridge 1, the cartridge 1 is filled with the liquid drug product, and a stopper 3 is inserted into the open second end (second open end) of the cartridge 1 to seal the contents of the cartridge 1. To dispense the liquid in cartridge 1, cannula 13 must first pierce septum 2 to access liquid medication chamber 4. With the fluid path open, a force is applied to stopper 3 such that the liquid held within cartridge 1 is compressed and forced out of cartridge 1 through the fluid path of cannula 13 across septum 2.

[0026] As shown in FIG. 2, the cassette 10 is used to accommodate a predetermined arrangement of cartridges 1 and load them into the drive unit 20 for delivery into a patient's body. The cassette 10 includes a main housing 5 and an upper housing (housing top) 6. The main housing 5 has multiple holding chambers 7 for holding multiple cartridges 1. The multiple holding chambers 7 are arranged radially around the axis of the cassette 10. The upper housing 6 is configured to seal the cartridges 1 held within the main housing 5 from above. The bottom of the main housing 5 has multiple notches (lower notches) 8 located below each cartridge 1, allowing physical access to the stoppers 3 within the cartridges 1. Meanwhile, the upper housing 6 also has multiple notches (upper notches) 9, allowing open access to the diaphragms 2 shown in FIG. 3. The cassette 10 is cylindrical, and a flat portion 11 may be provided on the outer surface of the cassette 10. The flat portion 11 is used to regulate the orientation of the cassette 10 when it is loaded into the drive unit 20. This unique shape is used as a keying mechanism and may have different shapes or features in other examples. The illustrated cassette 10 shows an example using seven individual cartridges 1. If fewer cartridges are required, fewer cartridges may be installed in the cassette 10, leaving empty holding chambers 7. If a greater number of cartridges are required, the cassette 10 may be configured to hold an unlimited number of additional cartridges. An RFID label or equivalent technology containing drug content information and ordering information may be attached to the main housing 5. In this case, communication with the drive unit 20 prior to delivery can ensure the authenticity and correctness of the cassette 10.

[0027] As shown in FIG. 4, the upper manifold (manifold top) 12 is a member having an inner cavity corresponding to the inner cavity of the upper housing 6 of the cassette. The upper manifold 12 is assembled to cover the upper housing 6 of the cassette and the diaphragm 2 of the cartridge, and is configured to be lockable (fixed) to the cassette 10 (e.g., the main housing 5 and / or the upper housing 6). As shown in FIG. 4, a sharp cannula 13 is provided in the upper manifold 12 located above each cartridge 1. Each cannula 13 is connected to a fluid channel 14 in the upper manifold 12. All fluid channels converge into a common outlet 15 located at the axis of the upper manifold 12. This common outlet 15 is connected to an infusion set (infusion set) 16 equipped with a needle 17 that is inserted into a patient's injection site (e.g., the abdomen). When the upper manifold 12 is attached to the loaded cassette 10 (see FIG. 5 ), each cannula 13 pierces a corresponding septum 2, forming a fluid path from all cartridges 1 in the cassette 10 to the infusion set 16. When the upper manifold 12 is attached to the loaded cassette 10, multiple cannulas 13 may pierce the septum 2 simultaneously. In some examples, a check valve may be provided in-line with each cannula 13 to prevent backflow into other cartridges 1 during infusion (infusion). During manufacturing, the cannulas 13 with the upper manifold 12, together with the infusion set 16, may be hermetically sealed throughout and may be subjected to terminal sterilization, for example, using gamma irradiation or ethylene oxide (EO).

[0028] Once the drug (liquid medication) is held in the cassette 10, it is administered to the patient by an electromechanical belt-mounted drive unit 20. As shown in FIG. 6, the drive unit 20 is attached to the patient by a belt (body strap) 18. The cassette 10 is then loaded into the drive unit 20. In this state, the infusion set 16 can move freely outside the drive unit 20. The tip of the infusion set 16 is provided with a needle 17 of 25G (gauge) or equivalent. The needle 17 is inserted into an injection site in the patient's abdomen.

[0029] FIG. 7 shows an overview of the external structure and operating parts of the drive unit 20. The front of the drive unit 20 is provided with a spring-loaded cassette door 19 that opens automatically. The cassette door 19 is used to cover the cassette drum 28 (cassette receiving drum) inside the drive unit 20. The cassette door 19 has a notch 21 that allows the infusion set 16 of the cassette 10 to pass through the cassette door 19 even when the cassette door 19 is closed. A mechanical button 22 is provided on the top of the drive unit 20. When the user presses the mechanical button 22, the latch of the cassette door 19 on the front of the drug delivery device (drive unit 20) is released, allowing the cassette door 19 to be opened. To prevent the user from opening the cassette door 19 during operation, the cassette door button 22 can be disabled within the drug delivery device (drive unit 20) via a mechanical interlock 27 (see FIG. 8). Additionally, the drive unit 20 has a simple user interface (UI) ( FIG. 7 ) on the top surface, which includes 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 turn the drug delivery device on or off. The start / pause button 23 is pressed by the user to start or pause the infusion process. The number of progress LEDs 24 displayed on the user interface (UI) may indicate the number of cartridges 1 loaded into the cassette 10. As the drug delivery device progresses through the infusion process, the progress LEDs 24 light up to indicate that the corresponding cartridge 1 has completed its infusion. These controls and indicators located on the top surface are mounted on a printed circuit board (PCB) attached to the back of the outer shell of the drive unit 20. In some examples, these controls may be replaced with a touch display or may be remotely controlled via technology such as Bluetooth.In some examples, the individual progress LEDs 24 mounted on the printed circuit board (PCB) may be replaced with a single LED display or an organic LED (OLED) display. A USB connector 26 (e.g., a USB-C port) may be provided on the back of the drug delivery device (drive unit 20). The USB connector 26 is used as a connector (receptacle) to be connected to a charger for charging the internal battery 39 of the drug delivery device.

[0030] The cassette 10 is loaded into the cassette drum 28. The cassette drum 28 is formed in a shape that can accommodate the outer shape of the cassette 10 so as to limit the orientation of the cassette 10 when loaded into the drive unit 20. FIGS. 9 and 10 show the cassette drum 28. A back surface 34 of the cassette drum 28 is provided with drum cutouts 32 that expose the cutouts 8 formed in the cassette 10. This allows access to each cartridge 1 (drug cartridge) through each cutout 8. A first shaft 30 is attached to the cassette drum 28 along its central axis. The cassette drum 28 is rotatable together with the first shaft 30. When the cassette 10 is loaded into the cassette drum 28, the first shaft 30 is connected to the cassette 10, for example, via the cassette drum 28. This allows the cassette 10 to rotate together with the first shaft 30. Furthermore, a cross element 100 is attached to the first shaft 30. As the cross element 100 rotates, the cassette 10 also rotates. In some examples, an RFID transmitter / receiver may be located near the cassette drum 28 to identify and communicate with the loaded cassette 10.

[0031] The cross element 100 may be formed similarly to the cross element of a Geneva mechanism (Geneva drive). Specifically, the cross element 100 has a plurality of blades 102 separated by slots 104. Each blade 102 extends radially outward from a center 106 of the cross element 100 to an exposed free end 108, such that the plurality of blades 102 collectively radiate outward. The free ends 108 of the plurality of blades 102 collectively define a discontinuous outer edge 110 of the cross element 100. This outer edge 110 surrounds the first shaft 30.

[0032] A second shaft 200 is coupled to a drive motor 202. The second shaft 200 may be disposed substantially parallel to the first shaft 30. A drive member 204 is attached to the second shaft 200. The drive member 204 rotates together with the second shaft 200 about a rotational drive axis AR. As shown in FIG. 11 , the drive member 204 has a first end face 206 disposed to face a direction substantially parallel to the rotational drive axis AR. A drive pin 208 protrudes from the first end face 206 in a first direction 210 substantially parallel to the rotational drive axis AR. The second end face 212 is offset from the first end face 206 in the first direction 210. A side wall 214 is formed on the outer periphery of the drive member 204 over the height between the first end face 206 and the second end face 212. 12, the drive member 204 is positioned such that the side wall 214 faces the outer edge 110 of the cross element 100. The drive member 204 is positioned such that the drive pin 208 engages with one slot 104 in the cross element 100 during rotation, as described below.

[0033] FIGS. 13-17 illustrate the interaction between the drive member 204 and the cross element 100. The drive member 204 can rotate in either direction, providing bidirectional movement for the cassette 10. As the drive member 204 rotates about the rotary drive shaft, the drive pin 208 moves circumferentially, tracing an arc. As the drive pin 208 moves circumferentially, tracing an arc, a series of interactions occur. First, as shown in FIG. 13, as the drive pin 208 passes through a first portion of the arc, it is received in the first slot 32A. As the rotation continues, as the drive pin 208 passes through a second portion of the arc, it is pressed against the first blade 102A. This generates a moment about the first shaft 30, causing the cassette 10 to rotate as shown in FIGS. 14-16. In the illustrated example, the drive pin 208 is rotated counterclockwise, resulting in a clockwise rotation of the cross element 100. As will be readily understood by those skilled in the art, the drive pin 208 may also be rotated clockwise, resulting in a counterclockwise rotation of the cross element 100. With further rotation, as the drive pin 208 passes (moves) through the third portion of the arc, the drive pin 208 stops pushing the first blade 102A and exits the first slot 32A. As a result, the second blade 102B adjacent to the other side of the first slot 32A is aligned with the drive member 204. Further rotation of the drive pin 208 also causes the cross element 100 to rotate further. The rotation direction of the drive pin 208 can be changed depending on the desired positioning of the cartridge 1 (drug cartridge). Although not shown in FIGS. 9 to 17, a plunger rod 42 (see FIGS. 18 to 21) is provided at a fixed position relative to the cassette drum 28. The plunger rod 42 can selectively access (approach) the cartridge 1 (drug cartridge) that is positioned in a straight line along the axial direction relative to the plunger rod 42. The plunger rod 42 may be arranged so as to be positionable at any circumferential position (radial position) relative to the cassette 10 that is rotatable relative to the plunger rod 42.

[0034] As will be appreciated by those skilled in the art, the drive pin 208's passage (movement) along the aforementioned arc may be completed during one rotation of the drive pin 208 about the rotational drive axis AR. This allows for stepwise adjustment of the cross element with each rotation of the drive pin 208. Preferably, the number of blades 102 is equal to the number of cartridges 1 (drug cartridges). Furthermore, the blades 102 may be similarly formed to one another. In this manner, each blade 102 can be adjusted one step with each rotation of the drive pin 208 (pin member). This allows for forward and backward adjustment of the plunger rod 42, thereby enabling sequencing of drug delivery.

[0035] To limit rotation of the cross element 100, and thus the cassette 10, when movement is not intended, the first portion 214A of the sidewall 214 may be configured to form-fittingly engage the free end 108 of the blade 102 closest to the drive member 204. For example, as shown in FIG. 17 , the first portion 214A of the sidewall 214 form-fittingly engages the free end 108B of the second blade 102B, thereby limiting rotation of the cross element 100. When the drive pin 208 is passing through the third portion of the arc, the first portion 214A of the sidewall 214 may form-fittingly engage the free end 108. As a non-limiting example, the first portion 214A of the sidewall 214 may be convex, and the free end 108 of each blade 102 may be concave. In this manner, the drive member 204 can hold the cross element 100 captive during indexing of the cassette 10, thereby preventing unwanted rotation of the cassette 10.

[0036] Additionally, the sidewall 214 may be positioned to provide clearance for the blade 102 engaged with the drive pin 208. As shown in FIGS. 13-15 , the second portion 214B of the sidewall 214 extends continuously along a portion of the first end face 206 and is spaced sufficiently apart from the drive pin 208 to allow the blade 102 to overlap the first end face 206 as the drive pin 208 passes through the second portion of its arc. The second portion 214B of the sidewall 214 provides sufficient clearance for the blade 102 to rotate without interference. The second portion 214B may extend from the first portion 214A to the second shaft 200. The second portion 214B may be discontinuous with individual panels located on either side of the second shaft 200, with the panels on both sides extending from (both ends of) the first portion 214A.

[0037] 18 and 20 show the internal components of the drive unit 20. The main components of the infusion drive system are a battery 39, an encoder motor 40, a power transmission 41, and a plunger rod 42. During infusion, power is supplied to the encoder motor 40, which rotates the power transmission 41, which in turn rotates a drive screw 43. This causes the plunger rod 42 to extend forward from its home position into the cassette drum 28. The encoder motor 40 and custom firmware are used to track the position of the plunger rod 42. The firmware monitors the current of the encoder motor 40, which directly correlates to the force exerted by the plunger rod 42. As the plunger rod 42 enters the cassette drum 28, it passes through the cassette body housing 5 via the plunger notch 8 adjacent to each cartridge 1. The cross element 100 ensures that the plunger rod 42 is axially aligned with the target cartridge 1 (drug cartridge). As the plunger rod 42 advances further, it enters the target cartridge 1 (drug cartridge) and contacts the cartridge stopper 3. As the plunger rod 42 continues forward, it begins to push the cartridge stopper 3 into the cartridge 1 (see Figures 19 and 21). This expels the contents of the cartridge 1 into the cannula 13 that penetrates the septum 2, and then through the cassette's upper manifold 12 into the infusion set 16 for infusion into the patient. Once the contents of the cartridge 1 have been completely expelled, the encoder-equipped motor 40 is rotated in the reverse direction, returning the plunger rod 42 to its home position. When the home position is reached, the plunger rod 42 moves back, thereby enabling adjustment of the cross element 100 in the circumferential direction (radial direction) so that another cartridge 1 is aligned in a straight line with respect to the plunger rod 42 in the axial direction.The cross element 100 can be rotated to align the various cartridges 1 in any order. This also allows for partial dosing of cartridges 1. For example, partial dosing of cartridge A can be followed by (full or partial) dosing of cartridge B, and then returning to cartridge A for further dosing. In some examples, a flexible or telescoping plunger rod can be used instead of a rigid (hard) plunger rod 42. Similarly, the means for driving the plunger rod 42 can be replaced by a linear actuator system, a pneumatic system, a magnetic system, or a spring-driven system. One or more guides 44 can be provided to maintain alignment of the plunger rod 42. As shown in FIGS. 20 and 21 , maintaining the plunger rod 42 includes supporting it away from the cassette drum 28 so that it is fixed relative to the cassette drum 28.

[0038] In one example, any of the combination drug delivery devices disclosed herein can deliver two or more drugs for patients suffering from a wide range of illnesses or diseases, such as cancer, autoimmune diseases, inflammatory diseases, cardiovascular diseases, or fibrotic diseases. In one example, one or more cartridges 1 may contain a single drug. In one example, one or more cartridges 1 may contain two or more combination drugs. In one example, one or more cartridges 1 may contain solid drugs (tablets, capsules, powders, freeze-dried drugs, spray-dried drugs, etc.). These solid drugs can be reconstituted (reconstituted) to form liquid drugs by the inflow of a diluent.

[0039] In one example, one or more of the drugs in the drug delivery device for any of the combinations disclosed herein is an immune checkpoint inhibitor. In particular examples, the immune checkpoint inhibitor is a programmed cell death 1 ("PD-1") pathway inhibitor, a cytotoxic T-lymphocyte-associated antigen 4 ("CTLA-4") antagonist, a lymphocyte-activation gene 3 ("LAG-3") antagonist, a CD80 antagonist, a CD86 antagonist, a T-cell immunoglobulin-mucin domain 3 ("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, or a combination of these. The compounds are selected from the group consisting of: 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 protein receptor-associated immunoglobulin domain-containing ("PVRIG") antagonist, a tryptophan-2,3-dioxygenase ("TDO") antagonist, a V-domain Ig inhibitor of T-cell activation ("VISTA") antagonist, and a killer cell immunoglobulin-like receptor ("KIR") antagonist.

[0040] In one example, the PD-1 pathway inhibitor is an anti-PD-1 antibody or an antigen-binding fragment thereof. In a specific example, 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.

[0041] In one example, the PD-1 pathway inhibitor is an anti-PD-L1 antibody or an antigen-binding fragment thereof. In a particular example, 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.

[0042] In one example, the PD-1 pathway inhibitor is a small molecule drug. In a particular example, the PD-1 pathway inhibitor is CA-170. In another example, the PD-1 pathway inhibitor is a cell therapy. In one example, the cell therapy is a MiHA-loaded PD-L1 / L2-silenced dendritic cell vaccine. In another example, the cell therapy is multipotent killer T lymphocytes expressing anti-programmed cell death protein 1 antibodies, autologous PD-1-targeted chimeric antigen receptor-modified T lymphocytes, or PD-1 knockout autologous T lymphocytes.

[0043] In one example, the PD-1 pathway inhibitor is an anti-PD-L2 antibody or antigen-binding fragment thereof, hi another example, the anti-PD-L2 antibody is rHIgM12B7.

[0044] In one example, the PD-1 pathway inhibitor is a soluble PD-1 polypeptide. In certain examples, the soluble PD-1 polypeptide is a fusion polypeptide. In some examples, the soluble PD-1 polypeptide comprises a ligand-binding fragment of the PD-1 extracellular domain. In other examples, the soluble PD-1 polypeptide comprises a ligand-binding fragment of the PD-1 extracellular domain. In another example, the soluble PD-1 polypeptide further comprises an Fc domain.

[0045] In one example, the immune checkpoint inhibitor is a CTLA-4 antagonist. In certain examples, the CTLA-4 antagonist is an anti-CTLA-4 antibody or an antigen-binding fragment thereof. In some examples, the anti-CTLA-4 antibody is ipilimumab (Yervoy), tremelimumab (ticilimumab; CP-675,206), AGEN-1884, or ATOR-1015. In one example, any of the drug delivery devices for combinations disclosed herein includes a CTLA-4 antagonist (e.g., ipilimumab (Yervoy)) and a PD-1 pathway inhibitor (e.g., nivolumab (Opdivo) or pembrolizumab (Keytruda)).

[0046] In one example, the immune checkpoint inhibitor is a LAG3 antagonist. In a specific example, the LAG3 antagonist is an anti-LAG3 antibody or an antigen-binding fragment thereof. In a specific example, the anti-LAG3 antibody is leratolimab (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 example, any of the drug delivery devices for combination drugs disclosed herein includes a LAG3 antagonist (e.g., leratolimab or MK-4280) and a PD-1 pathway inhibitor (e.g., nivolumab (Opdivo) or pembrolizumab (Keytruda)). In one example, any of the drug delivery devices for combination drugs disclosed herein includes a LAG3 antagonist (e.g., leratolimab or MK-4280) and a CTLA-4 antagonist (e.g., ipilimumab (Yervoy)). In one example, any of the drug delivery devices for combination drugs disclosed herein includes a LAG3 antagonist (e.g., leratolimab or MK-4280), a CTLA-4 antagonist (e.g., ipilimumab (Yervoy)), and a PD-1 pathway inhibitor (e.g., nivolumab (Opdivo) or pembrolizumab (Keytruda)).

[0047] In one example, the immune checkpoint inhibitor is a KIR antagonist. In certain examples, the KIR antagonist is an anti-KIR antibody or an antigen-binding fragment thereof. In some examples, the anti-KIR antibody is lirilumab (1-7F9, BMS-986015, IPH 2101) or IPH4102.

[0048] In one example, the immune checkpoint inhibitor is a TIGIT antagonist. In one example, the TIGIT antagonist is an anti-TIGIT antibody or an antigen-binding fragment thereof. In a specific example, the anti-TIGIT antibody is BMS-986207, AB154, COM902 (CGEN-15137), or OMP-313M32.

[0049] In one example, the immune checkpoint inhibitor is a Tim-3 antagonist. In certain examples, the Tim-3 antagonist is an anti-Tim-3 antibody or an antigen-binding fragment thereof. In some examples, the anti-Tim-3 antibody is TSR-022 or LY3321367.

[0050] In one example, the immune checkpoint inhibitor is an IDO1 antagonist. In another example, the IDO1 antagonist is indoximod (NLG8189; 1-methyl-D-TRP), epacadostat (INCB-024360, INCB-24360), KHK2455, PF-06840003, navoximod (RG6078, GDC-0919, NLG919), BMS-986205 (F001287), or a pyrrolidine-2,5-dione derivative.

[0051] In one example, the immune checkpoint inhibitor is a STING antagonist. In particular examples, the STING antagonist is a 2'-monofluoro-substituted cyclic dinucleotide or a 3'-monofluoro-substituted cyclic dinucleotide, a 2'-3'-difluoro-substituted mixed linkage 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.

[0052] In one example, the immune checkpoint inhibitor is a CD20 antagonist. In some examples, the CD20 antagonist is an anti-CD20 antibody or an antigen-binding fragment thereof. In one example, the anti-CD20 antibody is rituximab (Rituxan, IDEC-102, IDEC-C2B8), ABP 798, ofatumumab, or obinutuzumab.

[0053] In one example, the immune checkpoint inhibitor is a CD80 antagonist. In a particular example, the CD80 antagonist is an anti-CD80 antibody or an antigen-binding fragment thereof. In one example, the anti-CD80 antibody is galiximab or AV 1142742.

[0054] In one example, the immune checkpoint inhibitor is a GARP antagonist. In some examples, the GARP antagonist is an anti-GARP antibody or an antigen-binding fragment thereof. In a particular example, the anti-GARP antibody is ARGX-115.

[0055] In one example, the immune checkpoint inhibitor is a CD40 antagonist. In certain examples, the CD40 antagonist is an anti-CD40 antibody or an antigen-binding fragment thereof. In some examples, 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 example, the CD40 antagonist is a soluble CD40 ligand (CD40-L). In one example, the soluble CD40 ligand is a fusion polypeptide. In one example, the soluble CD40 ligand is CD40-L / FC2 or monomeric CD40-L.

[0056] In one example, the immune checkpoint inhibitor is an A2aR antagonist. In some examples, the A2aR antagonist is a small molecule. In certain examples, the A2aR antagonist is CPI-444, PBF-509, istradefylline (KW-6002), preladenant (SCH420814), tozadenant (SYN115), bipadenant (BIIB014), HTL-1071, ST1535, SCH412348, SCH442416, SCH58261, ZM241385, or AZD4635.

[0057] In one example, the immune checkpoint inhibitor is a CEACAM1 antagonist. In some examples, the CEACAM1 antagonist is an anti-CEACAM1 antibody or an antigen-binding fragment thereof. In one example, the anti-CEACAM1 antibody is CM-24 (MK-6018).

[0058] In one example, the immune checkpoint inhibitor is a CEA antagonist. In one example, the CEA antagonist is an anti-CEA antibody or an antigen-binding fragment thereof. In a specific example, the anti-CEA antibody is sergituzumab-amnaleukin (RG7813, RO-6895882) or RG7802 (RO6958688).

[0059] In one example, the immune checkpoint inhibitor is a CD47 antagonist. In some examples, the CD47 antagonist is an anti-CD47 antibody or an antigen-binding fragment thereof. In certain examples, the anti-CD47 antibody is HuF9-G4, CC-90002, TTI-621, ALX148, NI-1701, NI-1801, SRF231, or Effi-DEM.

[0060] In one example, the immune checkpoint inhibitor is a PVRIG antagonist. In a particular example, the PVRIG antagonist is an anti-PVRIG antibody or an antigen-binding fragment thereof. In one example, the anti-PVRIG antibody is COM701 (CGEN-15029).

[0061] In one example, the immune checkpoint inhibitor is a TDO antagonist. In one example, the TDO antagonist is a 4-(indol-3-yl)-pyrazole derivative, a 3-indole substituted derivative, or a 3-(indol-3-yl)-pyridine derivative. In another example, the immune checkpoint inhibitor is an IDO and TDO dual antagonist. In one example, the IDO and TDO dual antagonist is a small molecule.

[0062] In some examples, the immune checkpoint inhibitor is a VISTA antagonist. In some examples, the VISTA antagonist is CA-170 or JNJ-61610588.

[0063] In one example, one or more of the drugs in the drug delivery device for any of the combinations disclosed herein is an immune checkpoint promoter or stimulator.

[0064] In one example, the immune checkpoint promoter 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.

[0065] In one example, the immune checkpoint promoter or stimulator is an OX40 agonist. In certain examples, the OX40 agonist is an anti-OX40 antibody or an antigen-binding fragment thereof. In some examples, the anti-OX40 antibody is tabolixizumab (MEDI-0562), pogalizumab (MOXR0916, RG7888), GSK3174998, ATOR-1015, MEDI-6383, MEDI-6469, BMS 986178, PF-04518600, or RG7888 (MOXR0916). In another example, the OX40 agonist is a cell therapy. In certain examples, the OX40 agonist is GINAKIT cells (iC9-GD2-CD28-OX40-expressing T lymphocytes).

[0066] In one example, the immune checkpoint promoter or stimulator is a CD40 agonist. In some examples, the CD40 agonist is an anti-CD40 antibody or an antigen-binding fragment thereof. In one example, the anti-CD40 antibody is ADC-1013 (JNJ-64457107), RG7876 (RO-7009789), HuCD40-M2, APX005M (EPI-0050), or Chi Lob 7 / 4. In another example, the CD40 agonist is a soluble CD40 ligand (CD40-L). In one example, the soluble CD40 ligand is a fusion polypeptide. In a particular example, the soluble CD40 ligand is trimeric CD40-L (AVREND™).

[0067] In one example, the immune checkpoint promoter or stimulator is a GITR agonist. In a specific example, the GITR agonist is an anti-GITR antibody or an antigen-binding fragment thereof. In one example, the anti-GITR antibody is BMS-986156, TRX518, GWN323, INCAGN01876, or MEDI1873. In one example, the GITR agonist is a soluble GITR ligand (GITRL). In some examples, the soluble GITR ligand is a fusion polypeptide. In another example, the GITR agonist is a cell therapy. In one example, the cell therapy is an anti-CTLA4-mAb-RNA / GITRL-RNA transduced autologous dendritic cell vaccine or a GITRL-RNA transduced autologous dendritic cell vaccine.

[0068] In one example, the immune checkpoint promoter or stimulator is a 4-1BB agonist. In some examples, the 4-1BB agonist is an anti-4-1BB antibody or an antigen-binding fragment thereof. In one example, the anti-4-1BB antibody is urelumab or PF-05082566.

[0069] In one example, the immune checkpoint promoter or stimulator is a CD80 agonist or a CD86 agonist. In some examples, the CD80 agonist or CD86 agonist is a soluble CD80 or CD86 ligand (CTLA-4). In particular examples, the soluble CD80 or CD86 ligand is a fusion polypeptide. In one example, the CD80 or CD86 ligand is CTLA4-Ig (CTLA4-IgG4m, RG2077, or RG1046) or abatacept (ORENCIA, BMS-188667). In another example, the CD80 agonist or CD86 agonist is a cell therapy. In one example, the cell therapy is MGN1601 (an allogeneic renal cell carcinoma vaccine).

[0070] In one example, the immune checkpoint promoter or stimulator is a CD28 agonist. In some examples, the CD28 agonist is an anti-CD28 antibody or an antigen-binding fragment thereof. In a particular example, the anti-CD28 antibody is TGN1412.

[0071] In one example, the CD28 agonist is a cell therapy. In a specific example, the cell therapy is JCAR015 (anti-CD19-CD28-ζ engineered CAR CD3+ T lymphocytes), CD28CAR / CD137CAR-expressing T lymphocytes, allogeneic CD4+ memory Th1-like T cells / microparticle-bound anti-CD3 / anti-CD28, anti-CD19 / CD28 / CD3ζ CAR gamma retroviral vector-transduced autologous T lymphocytes KTE-C19, anti-CEA IgCD28TCR-transduced autologous T lymphocytes, anti-EGFRvIII CAR-transduced allogeneic T lymphocytes, autologous CD123CAR-CD28-CD3ζ-EGFRt-expressing T lymphocytes, autologous CD171-specific CAR-CD28ζ-4-1-BB-EGFRt-expressing T lymphocytes, autologous CD19CAR-CD28-CD3ζ-EGFRt-expressing Tcm-enriched T cells, autologous PD-1-targeted chimeric switch receptor-modified T lymphocytes (chimera with CD28), CD19CAR-CD28-CD3ζ-EGFRt-expressing Tcm-enriched These are CD19CAR-CD28-CD3ζ-EGFRt-expressing Tn / mem-enriched T lymphocytes, CD19CAR-CD28ζ-4-1BB-expressing allogeneic T lymphocytes, CD19CAR-CD3ζ-4-1BB-CD28-expressing autologous T lymphocytes, CD28CAR / CD137CAR-expressing T lymphocytes, CD3 / CD28 costimulatory vaccine-primed autologous T lymphocytes, or iC9-GD2-CD28-OX40-expressing T lymphocytes.

[0072] In one example, the immune checkpoint promoter or stimulator is a CD27 agonist. In a particular example, the CD27 agonist is an anti-CD27 antibody or an antigen-binding fragment thereof. In one example, the anti-CD27 antibody is varlilumab (CDX-1127).

[0073] In one example, the immune checkpoint promoter or stimulator is a CD70 agonist. In some examples, the CD70 agonist is an anti-CD70 antibody or an antigen-binding fragment thereof. In one example, the anti-CD70 antibody is ARGX-110.

[0074] In one example, the immune checkpoint promoter or stimulator is an ICOS agonist. In certain examples, the ICOS agonist is an anti-ICOS antibody or an antigen-binding fragment thereof. In some examples, the anti-ICOS antibody is BMS986226, MEDI-570, GSK3359609, or JTX-2011. In other examples, the ICOS agonist is a soluble ICOS ligand. In some examples, the soluble ICOS ligand is a fusion polypeptide. In one example, the soluble ICOS ligand is AMG 750.

[0075] In one example, one or more of the drugs in the drug delivery device for any of the combinations disclosed herein is an anti-CD73 antibody or an antigen-binding fragment thereof. In a particular example, the anti-CD73 antibody is MEDI9447.

[0076] In one example, one or more of the drugs in the drug delivery device for any of the combinations disclosed herein is a TLR9 agonist, hi one example, the TLR9 agonist is agatolimod sodium.

[0077] In one example, one or more of the drugs in the drug delivery device for any of the combinations disclosed herein is a cytokine. In certain examples, the cytokine is a chemokine, interferon, interleukin, lymphokine, or member of the tumor necrosis factor family. In some examples, the cytokine is IL-2, IL-15, or interferon gamma.

[0078] In one example, one or more of the drugs in the drug delivery device for any combination disclosed herein is a TGF-β antagonist. In some examples, the TGF-β antagonist is fresolimumab (GC-1008), NIS793, IMC-TR1 (LY3022859), ISTH0036, travedelsen (AP 12009), recombinant transforming growth factor-β2, autologous HPV-16 / 18 E6 / E7-specific TGF-β-resistant T lymphocytes, or TGF-β-resistant LMP-specific cytotoxic T lymphocytes.

[0079] In some examples, one or more of the drugs in the drug delivery device for any of the combinations disclosed herein is an iNOS antagonist. In some examples, the iNOS antagonist is N-acetylcysteine ​​(NAC), aminoguanidine, L-nitroarginine methyl ester, or S,S-1,4-phenylenebis(1,2-ethanediyl)bisisothiourea.

[0080] In one example, one or more of the drugs of any of the drug delivery devices for the combinations disclosed herein is an SHP-1 antagonist.

[0081] In one example, one or more of the drugs in the drug delivery device for any combination disclosed herein is a colony-stimulating factor 1 receptor ("CSF1R") antagonist. In particular examples, the CSF1R antagonist is an anti-CSF1R antibody or an antigen-binding fragment thereof. In some examples, the anti-CSF1R antibody is emactuzumab.

[0082] In some examples, one or more of the drugs in the drug delivery device for any of the combinations disclosed herein is a TNF family member agonist, hi some examples, the TNF family member agonist is ATOR 1016, ABBV-621, or adalimumab.

[0083] In one example, one or more of the drugs in a drug delivery device for any combination disclosed herein is interleukin-2 (IL-2), such as aldesleukin. Preferably, the IL-2 or (e.g., PEGylated) conjugated IL-2 is modified to selectively activate effector T cells over regulatory T cells ("T-eff IL-2"), e.g., bempegaldesleukin. In one example, a drug delivery device for any combination disclosed herein includes a modified IL-2 (e.g., bempegaldesleukin) that selectively activates effector T cells over regulatory T cells and a PD-1 pathway inhibitor (e.g., nivolumab (Opdivo) or pembrolizumab (Keytruda)). In one example, a drug delivery device for any combination disclosed herein includes a modified IL-2 (e.g., bempegaldesleukin) that selectively activates effector T cells over regulatory T cells, and a LAG3 antagonist (e.g., leratolimab or MK-4280). In one example, a drug delivery device for any combination disclosed herein includes a modified IL-2 (e.g., bempegaldesleukin) that selectively activates effector T cells over regulatory T cells, a PD-1 pathway inhibitor (e.g., nivolumab (Opdivo) or pembrolizumab (Keytruda)), and a LAG3 antagonist (e.g., leratolimab or MK-4280). In one example, a drug delivery device for any combination disclosed herein includes a modified IL-2 (e.g., bempegaldesleukin) that selectively activates effector T cells over regulatory T cells, and a CTLA-4 antagonist (e.g., ipilimumab (Yervoy)). In one example, a drug delivery device for any combination disclosed herein includes a modified IL-2 (e.g., bempegaldesleukin) that selectively activates effector T cells over regulatory T cells, a PD-1 pathway inhibitor (e.g., nivolumab (Opdivo) or pembrolizumab (Keytruda)), and a CTLA-4 antagonist (e.g., ipilimumab (Yervoy)).In one example, a drug delivery device for any combination disclosed herein includes a modified IL-2 (e.g., bempegaldesleukin) that selectively activates effector T cells over regulatory T cells, a CTLA-4 antagonist (e.g., ipilimumab (Yervoy)), and a LAG3 antagonist (e.g., leratolimab or MK-4280). In one example, a drug delivery device for any combination disclosed herein includes a modified IL-2 (e.g., bempegaldesleukin) that selectively activates effector T cells over regulatory T 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., leratolimab or MK-4280).

[0084] In one example, one or more of the drugs in the drug delivery device for any of the combinations disclosed herein is a CD160 (NK1) agonist. In a particular example, the CD160 (NK1) agonist is an anti-CD160 antibody or an antigen-binding fragment thereof. In one example, the anti-CD160 antibody is BY55.

[0085] In one example, one or more cartridges 1 may contain a soluble CTLA-4 polypeptide. Soluble CTLA-4 polypeptides may be useful, for example, in the treatment of T cell-mediated autoimmune diseases (e.g., rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, graft-versus-host disease, and transplant rejection). In one example, the soluble CTLA-4 polypeptide is abatacept (Orencia), belatacept (Nurogix), RG2077, or RG-1046. In a particular example, one or more cartridges 1 in a drug delivery device for a combination described herein contain a soluble CTLA-4 polypeptide (e.g., abatacept (Orencia)) and a Bruton's tyrosine kinase inhibitor (e.g., branebrutinib). In certain examples, one or more cartridges 1 in a drug delivery device for a combination described herein include a soluble CTLA-4 polypeptide (e.g., abatacept (Orencia)) and a tyrosine kinase-2 inhibitor (e.g., BMS-986165). In certain examples, one or more cartridges 1 in a drug delivery device for a combination described herein include a soluble CTLA-4 polypeptide (e.g., abatacept (Orencia)) and interleukin-2 (IL-2) or "T-reg IL-2" (e.g., BMS-986326 and NKTR-358) that selectively activates regulatory T cells but not effector T cells.

Claims

1. 1. A drug delivery device for delivering drugs to a patient from a plurality of drug cartridges, comprising: Each of the drug cartridges comprises an elongate body having a first end sealed by a septum and an open second end, and a stopper disposed within the body; In an initial state, each of the drug cartridges includes at least one drug contained within the body between the stopper and the septum; The drug delivery device comprises: a cylindrical cassette configured to house the plurality of drug cartridges; a reversibly advanceable plunger; a first shaft having a cross element attached thereto; a reversibly rotatable drive member attached to the second shaft for rotation therewith about a rotary drive axis; the first shaft is coupled to the cassette such that the cassette rotates with rotation of the cross element to individually align the plurality of drug cartridges with the plungers; the plunger is advanceable to force the stopper toward the septum in the aligned medication cartridge; The cross element has a plurality of blades separated from one another by slots; each of the blades radiating radially outward from a center of the cross element to an exposed free end thereof; the free ends of the plurality of blades collectively define a discontinuous outer edge of the cross element that circumscribes the first shaft; the drive member has a first end surface arranged to face a direction parallel to the rotation drive shaft, a drive pin protruding from the first end surface along a first direction parallel to the rotation drive shaft, a second end surface offset from the first end surface in the first direction, and a sidewall formed on the outer periphery of the drive member at a height between the first end surface and the second end surface; the drive member is positioned such that the side wall is aligned facing the outer edge of the cross element; The drive pin is driven to describe an arc by rotation of the drive member around the rotation drive shaft, and when the drive pin passes through a first portion of the arc, the drive pin is received in a first slot of the slots of the cross element, and when the drive pin passes through a second portion of the arc, the drive pin is pressed against a first blade of the plurality of blades adjacent to the first slot, thereby generating a moment around the first shaft to rotate the cassette, and when the drive pin passes through a third portion of the arc, the drive pin stops pressing against the first blade and comes out of the first slot. Drug delivery devices.

2. when the drive pin passes through the third portion of the arc, a first portion of the side wall form-fittingly engages a free end of a second blade of the plurality of blades adjacent the first slot to resist rotation of the cross element; The drug delivery device of claim 1 .

3. the first portion of the side wall extends around the drive member between a plurality of spaced apart points on the first end surface; The drug delivery device of claim 2 .

4. the second portion of the side wall extends continuously along a portion of the first end surface, the second portion of the sidewall is spaced from the drive pin such that the first blade can overlap the first end surface when the drive pin passes through the second portion of the arc. The drug delivery device of claim 3 .

5. the first portion of the sidewall is a convex portion; the free end of the second blade is concave; The drug delivery device of claim 2 .

6. the second portion of the side wall extends continuously along a portion of the first end surface, the second portion of the sidewall is spaced from the drive pin such that the first blade can overlap the first end surface when the drive pin passes through the second portion of the arc. The drug delivery device of claim 1 .

7. the number of blades is equal to the number of drug cartridges; The drug delivery device of claim 1 .

8. The plurality of blades are configured to have the same shape. The drug delivery device of claim 1 .

9. when the drive pin passes through the first, second, and third portions of the arc, the cassette is rotated to move a first drug cartridge of the plurality of drug cartridges out of alignment with the plunger and move a second drug cartridge of the plurality of drug cartridges adjacent to the first drug cartridge into alignment with the plunger. The drug delivery device of claim 1 .

10. the drive pin passes through the first portion, the second portion, and the third portion of the arc during one rotation around the rotation drive shaft; The drug delivery device of claim 1 .

11. further comprising a motor that rotates the second shaft about the rotary drive shaft; The drug delivery device of claim 1 .

12. The first shaft and the second shaft are parallel to each other. The drug delivery device of claim 1 .

13. further comprising a plurality of cannulas positioned to pierce the septa of the plurality of drug cartridges; The drug delivery device of claim 1 .

14. the plurality of cannulas are positioned to simultaneously pierce the septa of the plurality of drug cartridges; 14. The drug delivery device of claim 13.

15. further comprising a plurality of fluid channels individually connected to the plurality of cannulas.

14. The drug delivery device of claim 13.

16. The plurality of fluid channels are arranged to converge at a common outlet.

16. The drug delivery device of claim 15.

17. the plunger is configured to urge the stopper toward the septum of the aligned drug cartridge such that the at least one drug contained in the body of the aligned drug cartridge is expelled through the cannula that pierces the septum of the aligned drug cartridge.

14. The drug delivery device of claim 13.

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