Radial adjustable multi-cartridge combination drug delivery device for hypodermic injection with cross-shaped elements

Abstract

In one aspect of the present invention, there is provided a drug delivery device for delivering a drug from a plurality of drug cartridges to a patient, each of the drug cartridges comprising an elongate body having a first end sealed with a septum and a second open end, and a stopper located in the body, where in an initial state, the stopper is in fluid communication with the elongate body. Each of the drug cartridges comprises at least one drug contained in the body between its stopper and septum. The drug delivery device comprises: a cylindrical cartridge configured to accommodate a plurality of drug cartridges; the plunger can be propelled reversely; a first shaft having a cross-shaped element mounted thereto, the first shaft coupled to the cartridge such that rotation of the cross-shaped element results in corresponding rotation of the cartridge to individually align the plurality of drug cartridges with a plunger that can be advanced to urge a stopper of the aligned drug cartridge toward a septum of the aligned drug cartridge, the cross-shaped element comprises a plurality of blades separated by slots, each of the blades radially outwardly away from the center of the cross-shaped element up to an exposed free end, the free ends of the blades collectively defining a discontinuous outer edge of the cross-shaped element surrounding the first axis; and a reversibly rotatable drive member mounted to the second shaft for rotation with the second shaft about a drive axis of rotation, the drive member includes a first end surface facing a direction generally parallel to the drive rotation axis, a drive pin protruding from the first end surface in a first direction generally parallel to the drive rotation axis, a second end surface offset from the first end surface in the first direction, and a sidewall defined around a circumference 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 in facing alignment with the outer edge of the cross-shaped element. The drive pin crosses the arc as the drive member rotates about the drive axis of rotation, in which: with the drive pin crosses a first portion of the arc, the drive pin is received in a first of the slots of the cross-shaped element, and with the drive pin crosses a second portion of the arc, the drive pin is received in a second of the slots of the cross-shaped element; the drive pin is pressed against a first one of the blades adjacent the first slot, thereby generating a torque about the first axis, resulting in rotation of the cartridge, and the drive pin stops pressing against the first blade and departs from the first slot with the drive pin traversing the third portion of the arc. Advantageously, the present invention provides an arrangement for reversibly adjusting drug cartridges in various fixed increments.

Description

Field of the Invention

[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 combination. Background Art

[0002] For a variety of reasons, many drugs must be administered parenterally. For example, biotech-derived biopharmaceuticals are therapeutic proteins that cannot be delivered orally because they are destroyed by the digestive system, rendering them ineffective. Thus, such biopharmaceuticals are typically delivered via an administration route that bypasses the digestive system, most typically via intravenous and subcutaneous routes.

[0003] Recent medical advances, particularly in cancer treatment, have shown that therapeutically beneficial effects can be achieved through the synergistic combination of two or more drugs.

[0004] For example, recent clinical studies have shown that the combination of anti-PD-1 checkpoint inhibitor drugs and CTLA4 checkpoint inhibitors can have beneficial synergistic effects in certain tumor types, which can lead to better clinical outcomes than administering either of the two drugs alone. Generally, such checkpoint inhibitor drugs are monoclonal antibodies of the biotech-derived immunoglobulin type or fragments thereof. In some cases, it can be beneficial to use such biopharmaceuticals in combination with conventional chemotherapeutic agents such as cytotoxic drugs.

[0005] There are several challenges associated with the co-administration of drugs parenterally, and various methods have been used to overcome them. These challenges include increased dosing complexity, a greater risk of dosing errors, and the burden on patients. The increased dosing complexity can manifest in a variety of ways, depending on the combination and the manner of administering the drugs. For example, one way to combine therapeutic biopharmaceuticals is to co-formulate them in solution in a fixed ratio combination. This results in formulation complexity because it is necessary to ensure a stable formulation in which the combined drugs maintain their potency and quality throughout the pharmaceutical supply chain. Those of ordinary skill in the art will understand that such drug formulations will typically include several excipients, e.g., buffers, pH regulators, tonicity regulators, stabilizers, etc. As the number of combined drugs increases, the complexity of the formulation also increases. Associated with the formulation challenges are the challenges related to developing analytical methods for such complex formulations, such as assays for assessing the quality, potency, and strength of each drug in the mixture. Another limitation of fixed ratio combinations is the loss of flexibility in the ratio of the drugs to be administered.

[0006] By compounding drugs from single-dose formulations closer to the point of care (e.g., in a compounding pharmacy), the complexity of formulation and analysis can be avoided while maintaining dispensing flexibility. In such cases, a pharmacist or pharmacy technician follows a protocol for mixing individual drugs using aseptic technique under a pharmacy hood. Most typically, this method is currently applied to mixing drugs in intravenous infusion bags, although the method could in principle be applied to mixing into vials for subsequent subcutaneous injection. While the complexity of compounding and analysis is avoided by this method, the complexity is shifted to the pharmacy. When this method is used to prepare intravenous infusions, it can only be performed near the point of care for patients visiting an infusion clinic. The advantage in terms of dosing and dose ratio flexibility provided by this method creates an accompanying risk of medication errors in the pharmacy, e.g., by using the incorrect drug or mixing it in the incorrect ratio. The checks and controls used in a well-organized pharmacy are designed to prevent such medication errors, but this risk provides another reason why this practice is restricted to pharmacies near the point of care (such as within a hospital). A final risk of pharmacy compounding is the risk of exposure to drugs or needlestick injury due to the multiple needle-based transfers that must be performed. This risk can be reduced by using compounding machines in the pharmacy, yet such machines become another source of complexity and expense.

[0007] The complexity of formulation and analysis can also be avoided by administering drugs separately (e.g., as separate intravenous infusions or subcutaneous injections). In some cases, this method may be required for technical reasons, e.g., if a stable fixed-ratio formulation cannot be achieved. In the case of intravenous infusions, for pharmacies that now need to manage multiple compounded infusions, this method only provides a slight reduction in protocol complexity. This method also does not eliminate the risk of medication errors. In both the case of intravenous infusions and subcutaneous injections, the burden on the patient is greater because they now have to endure multiple infusions or injections.

[0008] In some cases, for safety reasons, it may not be possible to administer all drugs immediately. For example, the burden of excipients may be unacceptably high. In the case where a biologic drug is derived from a bacterial cell culture, the concentration of residual bacterial endotoxins, although controlled to the lowest possible level during downstream processing, may still prevent the immediate administration of multiple drugs in a combination. The need to manage the excipient and endotoxin burden may require the patient to stay in the hospital for several days or to visit the clinic over a number of days, further increasing the burden on the patient.

[0009] In principle, drugs intended for co - administration can be provided individually in a convenient pre - filled form for subcutaneous delivery (such as pre - filled syringes, auto - injectors, or body - worn syringes) and self - administered by the patient personally away from the clinical setting. This approach can alleviate the need for the patient to stay in the hospital or make multiple visits. However, this approach will result in multiple injections and thus cause inconvenience to the patient and other attendant safety risks, such as injection site reactions. This approach also poses a significant risk of medication errors because the patient must record their administration status for each drug in the combination. If, for safety or therapeutic reasons, such as to manage endotoxin limits, the timing of administration of the respective drugs is important, there is also a risk of medication errors due to incorrect timing of the constituent doses. By co - packaging with clear instructions for use, the risk of medication errors can be reduced to some extent but not completely eliminated.

[0010] Currently, for the reasons stated above, most drug combinations administered parenterally are administered via the intravenous route in a clinical setting.

[0011] For pharmaceutical companies manufacturing and distributing drugs as combination therapies, co - formulation methods pose additional challenges and complexities in manufacturing and the supply chain. For companies with a portfolio of individual drugs that are used in combination with each other, these complexities increase as the number of combinations offered increases.

[0012] Each new combination of drugs adds an additional single - keeping unit (SKU) to the finished - goods inventory. Additionally, each new ratio or strength of a drug adds even more SKUs. This rapid growth of SKUs is referred to as the "combinatorial explosion" in the discipline of supply - chain management. In accounting, the inventory of such SKUs is accounted for as finished - goods inventory. Additional complexities arise in work - in - progress (WIP) inventory because individual drug substances or active pharmaceutical ingredients (APIs) must be stored in large quantities until compounded. Subsequently, the compounded drug products must also be stored in large quantities until filled into unit doses. In the case of biopharmaceuticals, which are typically stored at low temperatures in a frozen state, this results in multiple freeze - thaw processes and the associated need for large refrigerated storage facilities and equipment.

[0013] Especially when the drugs in question are expensive biopharmaceuticals, the financial impact of the combinatorial explosion and the associated inventory growth can be significant, not only because working capital is tied up as inventory but also because of the expensive facilities required to store WIP and finished - goods inventory under refrigerated conditions.

[0014] Due to the challenge of optimizing product mix among various possible combination SKUs in response to market demand, further challenges with co-formulated drug combinations arise in supply chain planning and forecasting. Since the bulk-stored APIs are "spread" across a potentially large number of finished product SKUs, accurate forecasting of demand is crucial to minimize the risk of overstocking some SKUs and understocking others ("stockouts"). For expensive biopharmaceuticals, the costs associated with forecasting errors can be very high. This problem is further exacerbated because pharmaceuticals are perishable goods, meaning that unsold inventory can only be stored for a fixed period of time before it expires. Clearly, such forecasting challenges increase with the number of drugs used in the combination and the SKUs in the product line.

[0015] In summary, for all of the above reasons, technologies are needed that can address each of these challenges associated with the delivery of combination therapies. The ideal technology would avoid the formulation and analytical complexities of fixed-ratio combination products, avoid combinatorial explosions and inventory growth in manufacturing and the supply chain, eliminate the risk of medication errors at the pharmacy and point of care (whether clinical or at home), and minimize the patient burden associated with multiple infusions or injections and dosing timing restrictions. The ideal technology should also maximize patient convenience by enabling flexible and convenient delivery of combination therapies (e.g., in the home or other non-clinical settings). To maximize patient convenience, the ideal technology should enable subcutaneous administration, as this is more suitable for non-clinical settings. It should also anticipate medical advancements such as the development of more complex combination therapies, including three or more drugs and active excipients such as hyaluronidase (e.g., recombinant human hyaluronidase, sold under the trade name by Halozyme Therapeutics Inc of San Diego, California).

[0016] As another example of medical progress, recent advances in immuno-oncology science have shown that precise timing of the doses of the component drugs of a combination therapy can have therapeutic benefits. For example, consider a combination therapy of "Drug A" and "Drug B" that is designed to target two biochemical targets "A" and "B" expressed by a particular tumor type, respectively. Recent developments have shown that in some cases, the expression of the tumor's targets may have temporal aspects that can be affected by the timing of the administration of the corresponding drugs. For example, administering Drug A, which binds to target A, at time zero may stimulate or upregulate the expression of target B at some later time (which could be minutes, hours, or even days). In such a case, administering Drug B when peak expression of target B occurs may be optimal. This time-resolved dispensing can be optimal for reasons of safety (e.g., reducing the drug dose required for equivalent therapeutic effect), efficacy, or both.

[0017] Given the biological nature of such time-resolved effects, they may not be compatible with conventional clinical schedules and, as such, utilization of them would require infusions at clinical visits on an unconventional schedule, thereby increasing the clinical and patient burden of the treatment. Accordingly, to fully utilize these effects, subcutaneous delivery in a non-clinical setting is needed to maximize the flexibility of dosing timing.

[0018] Accordingly, the above-described desirable technique enabling subcutaneous infusion is also suitable for time-resolved dispensing of treatment combinations.

[0019] The Applicant has now recognized that the combination principles described in the Applicant's co-pending applications: U.S. Provisional Patent Application No. 62 / 670,266, PCT Application No. PCT / US2019 / 031727, PCT Application No. PCT / 2019 / 031762, and PCT Application No. PCT / US2019 / 031791 (which are incorporated herein by reference in their respective entireties) can meet the requirements of the above-described desirable technique when implemented in a subcutaneous delivery device.

[0020] The assignee hereof has developed a radially adjustable multi-cartridge combination drug delivery device as shown in U.S. Patent Application No. 17 / 771,935 and PCT Application No. PCT / 2020 / 059672, which are incorporated herein by reference in their respective entireties. This drug delivery device uses a dial or gears to rotate a cartridge containing a plurality of drug cartridges. By rotation, the drug cartridges are individually aligned with a pushable plunger configured to expel the drug from the aligned drug cartridge. In the case of a dial, there are limitations for reversible rotation, thereby limiting the rapid alignment of the drug cartridges and thus not allowing a specific dispensing order of different drug elements. In the case of gears, the radial adjustment can be set incrementally, but is limited by the size of the available gear teeth. SUMMARY OF THE INVENTION

[0021] In one aspect of the present invention, there is provided a drug delivery device for delivering drugs from a plurality of drug cartridges to a patient, each drug cartridge of the drug cartridges comprising an elongate body and a stopper located in the body, the elongate body having a first end sealed with a septum and a second open end, wherein, in an initial state, each drug cartridge of the drug cartridges comprises at least one drug contained in the body between its stopper and the septum. The drug delivery device comprises: a cylindrical cartridge configured to accommodate a plurality of drug cartridges; a reversibly propellable plunger; a first shaft having a cross-shaped element mounted thereto, the first shaft being coupled to the cartridge such that rotation of the cross-shaped element causes corresponding rotation of the cartridge to align the plurality of drug cartridges individually with the plunger, the plunger being propellable to urge the stopper of the aligned drug cartridge against the septum of the aligned drug cartridge, wherein the cross-shaped element comprises a plurality of vanes separated by slots, each vane of the vanes radiating outwardly from the center of the cross-shaped element to an exposed free end, the free ends of the vanes collectively defining a discontinuous outer edge of the cross-shaped element surrounding the first shaft; and a rotatable drive member reversibly mounted to a second shaft for rotation therewith about a drive rotation axis, the drive member comprising a first end surface facing generally in a direction parallel to the drive rotation axis, a drive pin projecting from the first end surface in a first direction generally parallel to the drive rotation axis, a second end surface offset from the first end surface in the first direction, and a side wall defined about the circumference 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 faces and aligns with the outer edge of the cross-shaped element. As the drive member rotates about the drive rotation axis, the drive pin traverses an arc, wherein: in the case where the drive pin traverses a first portion of the arc, the drive pin is received in a first slot of the slots in the cross-shaped element, in the case where the drive pin traverses a second portion of the arc, the drive pin bears against a first vane adjacent to the first slot in the vanes, thereby generating a moment about the first shaft, causing rotation of the cartridge, and in the case where the drive pin traverses a third portion of the arc, the drive pin stops bearing against the first vane and exits the first slot. Advantageously, the present invention provides a means for reversibly adjusting the arrangement of the drug cartridges in various fixed increments.

[0022] Additionally, the exposed free end surfaces of the cross-shaped element may interface with the side wall surfaces of the rotating drive member to captively hold the cross-shaped element between indexing movements of the cartridge, thereby preventing any unwanted rotation of the cartridge.

[0023] These and other features of the present invention will be better understood by studying the following detailed description and the drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figures 1 to 21Various views of a drug delivery device formed in accordance with the present invention as described herein. Detailed Description

[0025] Referring to the drawings, a drug combination will be delivered and configured by utilizing a disposable cartridge 10 that contains an arrangement of cartridges 1 filled with liquid drugs for sequential injection. As is known in the art, one or more of the cartridges can be dry / wet cartridges having separate dry and wet components, allowing drugs in dissolved or other powder form to be reconstituted with a diluent within the cartridge (e.g., under the movement of a stopper 3). As Figure 1 shown, the cartridge 1 is a cylindrical glass or polymer tube, one end of which is formed to receive (e.g., crimped) a septum seal 2. Once the septum seal 2 is fastened to the cartridge 1, the cartridge 1 is filled with a liquid drug product, and a stopper 3 is inserted into the second open end to seal its contents. To dispense the fluid within the cartridge 1, an intubation 13 must first pierce the septum 2 to access the drug fluid chamber 4. With the fluid passageway open, a force is applied to the stopper 3, compressing the fluid held inside the cartridge 1 and pushing it out of the cartridge 1 through the fluid passageway of the intubation 13 that traverses the septum 2.

[0026] As Figure 2 shown, the cartridge 10 is used to hold a pre-configured arrangement of cartridges 1 and load them into a drive unit 20 for delivery to a patient. The cartridge 10 consists of: a body housing 5 having holding chambers 7 for a plurality of cartridges 1 radially positioned about its lateral axis; and a housing top 6 that caps the cartridges 1 held within the body housing 5, thereby capturing them within the body housing 5. Incisions 8 in the bottom of the body housing 5 beneath each cartridge 1 allow physical access to the stopper 3 within the cartridge 1, while upper incisions 9 in the housing top 6 allow open access Figure 3 to the cartridge septum 2 as shown. The cartridge 10 is cylindrical in shape and can be provided with a flat portion 11 on its outer surface for controlling 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 cartridge 10 depicted in the provided drawings shows the use of seven discrete cartridges 1; if fewer cartridges are needed, fewer cartridges can be assembled into the cartridge 10, leaving empty holding chambers 7. In embodiments where more cartridges may be required, the cartridge 10 can be designed to hold additional cartridges, without limitation. An RFID tag or equivalent technology containing drug content and sequence information can be attached to the body housing 5 to communicate with the drive unit 20 prior to delivery to ensure that the genuine and correct cartridge 10 is being used.

[0027] As Figure 4As shown, the manifold top 12 (which is a body having an inner cavity opposite to the inner cavity of the cartridge housing top 6) is designed to be mounted on the cartridge housing top 6 over the cartridge septum 2 and locked to the cartridge 10, for example, locked to the main body housing 5 and / or the cartridge housing top 6. As Figure 4 shown, sharp cannulas 13 are located within the manifold top 12 above each cartridge 1. The sharp cannulas are connected to fluid channels 14 within the manifold top 12, and all of the fluid channels converge to a common outlet 15 at the axis of the manifold top 12. This common outlet 15 leads to an infusion set 16 with a needle 17 that will be inserted into a patient's injection site (e.g., the abdomen). When the manifold top 12 is mounted onto the loaded cartridge 10 ( Figure 5 ), each cannula 13 pierces its corresponding septum 2 and creates a fluid path from all of the cartridges 1 in the cartridge 10 to the infusion set 16. In the case where the manifold top 12 is mounted onto the loaded cartridge 10, the cannulas 13 can pierce the septum 2 simultaneously. In an embodiment, check valves can be installed in the lines of each cannula 13 to remedy backflow to other cartridges 1 during injection. During the manufacturing process, the cannulas 13 with the manifold top 12 can be hermetically sealed, and the entire portion together with the infusion set 16 can be subjected to a terminal sterilization process, for example, by using gamma radiation or ethylene oxide (EO).

[0028] When the drug product is held within the cartridge 10, the drug product is delivered to the patient by means of an electromechanical belt-worn drive unit 20. As Figure 6 shown, the drive unit 20 is attached to the patient by means of a belt or body strap 18; then, the cartridge 10 is loaded into the drive unit 20, where the infusion set 16 can freely exit the drive unit 20. The infusion set 16 terminates in a 25G or similar needle 17 that is inserted into the patient's abdominal injection site.

[0029] In Figure 7 is depicted an overview of the external features and controls of the drive unit 20. There is a cartridge door 19 on the front face of the drive unit 20. The cartridge door is spring-biased to open automatically and is used to cover the cartridge receiving socket 28 within the drive unit 20. The cartridge door 19 has a cutout 21 to allow the infusion set 16 of the cartridge 10 to pass through the cartridge door 19 when closed. There is a mechanical button 22 on top of the drive unit 20 that the user presses to unlock the cartridge door 19 on the front face of the device to allow the cartridge door to open. To prevent the user from opening the cartridge door 19 during operation, the cartridge door button 22 can be disabled internally by the device via a mechanical interlock 27 ( Figure 8 ). Additionally, there is a simple user interface (UI) on top of the drive unit ( Figure 7) The user interface consists of a power button 25, a start / pause button 23, and a series of progressive LEDs 24. The user presses the power button 25 to power on or off the device, while the user presses the start / pause button 23 to start or pause the infusion process. The number of LEDs 24 present on the UI can represent the number of cartridges 1 loaded in the cassette 10. As the device progresses through the infusion process, the LEDs 24 will illuminate to indicate that the cartridge 1 has completed its infusion. These controls and indicators on the top side are currently included on a printed circuit board (PCB) mounted behind the housing of the drive unit 20. In an embodiment, these controls can be replaced with a touch display or controlled remotely via a technology such as Bluetooth. In an embodiment, the individually PCB-mounted LEDs can be replaced by a single organic LED (oLED) display. A USB connector 26 (e.g., a USB-C port) can be on the rear face of the device, which serves as a receptacle for connecting a charger to recharge the internal battery 39 of the device.

[0030] The cassette 10 is loaded into a cartridge barrel 28, which is shaped to receive the outer shape of the cassette 10 in order to control the orientation of the cassette 10 when loaded into the drive unit 20. Figure 9 and Figure 10 The cartridge barrel 28 is shown. A barrel cutout 32 is provided along the rear face 34 of the cartridge barrel 28, which is formed to expose each cutout 8 formed in the cassette 10 to allow access to the drug cartridge 1 therethrough. A first shaft 30 is mounted to the cartridge barrel 28 along the central axis thereof. The cartridge barrel 28 is rotatable together with the first shaft 30. In the case where the cassette 10 is loaded in the cartridge barrel 28, the first shaft 30 is coupled to the cassette 10 via the cartridge barrel 28, for example, such that the cassette 10 rotates together with the first shaft 30. Additionally, a cross-shaped element 100 is mounted to the first shaft 30. Rotation of the cross-shaped element 100 causes a corresponding rotation of the cassette 10. In an embodiment, an RFID transmitter / receiver can be placed near the cartridge barrel 28 to identify and communicate with the loaded cassette 10.

[0031] The cross-shaped element 100 can be formed in the same manner as the cross-shaped element of a Geneva mechanism or a driver. Specifically, the cross-shaped element 100 includes a plurality of vanes 102 separated by slots 104. Each of the vanes 102 extends radially outward from the center 106 of the cross-shaped element 100 to an exposed free end 108. The free ends 108 of the vanes 102 together define a discontinuous outer edge 110 of the cross-shaped element 100 surrounding the first shaft 30.

[0032] A second shaft 200 is also provided, which is coupled to a drive motor 202. The second shaft 200 can be aligned generally parallel to the first shaft 30. A drive member 204 is mounted to the second shaft 200 for rotation about a drive rotation axis AR together with the second shaft. AsFigure 11 As shown, the drive member 204 includes a first end surface 206 that faces in a direction generally parallel to the drive rotation axis AR. A drive pin 208 projects from the first end surface 206 in a first direction 210 generally parallel to the drive rotation axis AR. A second end surface 212 is provided to be offset from the first end surface 206 in the first direction 210. Side walls 214 are defined around the circumference of the drive member 204 at a height between the first end surface 206 and the second end surface 212. As Figure 12 schematically shown, the drive member 204 is positioned such that the side walls 214 are aligned facing the outer edge 110 of the cross-shaped element 100. The drive member 204 is positioned such that as it rotates, the drive pin 208 engages one of the slots 104 in the cross-shaped element 100, as described below.

[0033] Referring Figures 13 to 17 , the interaction between the drive member 204 and the cross-shaped element 100 is shown. The drive member 204 can rotate in either direction, thereby creating bidirectionality of the cartridge 10. As the drive member 204 rotates about the drive rotation axis, the drive pin 208 traverses an arc. As the drive pin 208 traverses the arc, a series of interactions occur. First, as Figure 13 shown, in the case where the drive pin 208 traverses the first part of the arc, the drive pin 208 is received in the first slot 32A. As rotation continues, the drive pin 208 traverses the second part of the arc, where the drive pin 208 bears against the first vane 102A, thereby generating a moment about the first axis 30, which causes rotation of the cartridge 10, as Figures 14 to 16 shown therebetween. It should be noted that the drive pin 208 is shown rotating counterclockwise, thereby causing clockwise rotation of the cross-shaped element 100. As will be readily understood by those skilled in the art, the drive pin 208 can rotate clockwise, thereby causing counterclockwise rotation of the cross-shaped element 100. As rotation continues, the drive pin 208 traverses the third part of the arc, where the drive pin 208 stops bearing against the first vane 102A and exits the first slot 32A. Thus, the second vane 102B, which is also adjacent to the first slot 32A, is now aligned with the drive member 204. Further rotation of the drive pin 208 can cause further rotation of the cross-shaped element 100. The direction of rotation of the drive pin 208 can be changed depending on the desired positioning of the drug cartridge 1. Although not shown in Figures 9 to 17 , a plunger rod 42 ( Figures 18 to 21 ) is provided in a fixed position relative to the cartridge barrel 28 to selectively approach the drug cartridge 1 axially aligned therewith. The plunger rod 42 can be arranged to be aligned at any radial position, and the cartridge 10 rotates relative to the plunger rod.

[0034] As will be understood by those skilled in the art, the aforementioned traversal of the drive pin 208 across the arc can be completed within one rotation of the drive pin 208 about the drive rotation axis AR. This allows the cross-shaped element to be incrementally adjusted with each rotation of the drive pin 208. The number of vanes 102 is preferably equal to the number of drug cartridges 1. Additionally, each of the vanes 102 can be formed similarly. In this way, one rotation of the pin member 208 can cause one of the vanes 102 to be adjusted by one increment. This allows for front-to-back adjustment relative to the plunger rod 42 to permit sequencing of drug delivery.

[0035] To limit the rotation of the cross-shaped element 100 and thus the rotation of the cartridge 10, when movement is not intended, a first portion 214A of the sidewall 214 can be configured to engage shape-fitingly with the free end 108 of the vane 102 closest to the drive member 204, e.g., as Figure 17 shown, where the first portion 214A of the sidewall 214 engages shape-fitingly with the free end 108B of the second vane 102B, thereby limiting the rotation of the cross-shaped element 100. In the case where the drive pin 208 traverses the third portion of the arc, the first portion 214A of the sidewall 214 can engage shape-fitingly with the free end 108. By way of non-limiting example, the first portion 214A of the sidewall can be convex, while each of the free ends 108 of the vanes 102 is concave. In this way, the drive member 204 can captively hold the cross-shaped element 100 between indexing movements of the cartridge 10, thereby preventing any unwanted rotation of the cartridge 10.

[0036] Additionally, the sidewall 214 can be positioned to provide clearance for the vanes 102 engaged by the drive pin 208. As Figures 13 to 15 shown, a second portion 214B of the sidewall 214 can be provided, which extends continuously along a portion of the first end surface 206, where the second portion 214B is sufficiently spaced from the drive pin 208 to allow the vane 102 to overlap the first end surface 206 in the case where the drive pin 208 traverses the second portion of the arc. The second portion 214B of the sidewall 214 provides sufficient clearance for the vane 102 to rotate therethrough without interference. The second portion 214B can extend from the first portion 214A to the second shaft 200. The second portion 214B can be discontinuous, with separate panels located on opposite sides of the second shaft 200, where the two panels extend from the first portion 214A (but from opposite ends).

[0037] In Figure 18 and Figure 20The internal components of the drive unit 20 are shown. The main components of the infusion drive system are the battery 39, the encoder motor 40, the drive train 41, and the plunger rod 42. During infusion, the encoder motor 40 is energized and will cause the drive train 41 to rotate to turn the screw drive 43, causing the plunger rod 42 to extend forward from its initial position and into the cartridge barrel 28. The encoder motor 40 and custom firmware are used to track the position of the plunger rod 42. The firmware also has the ability to monitor the current of the encoder motor 40, which is directly related to the force applied by the plunger rod 42. When the plunger rod 42 enters the cartridge barrel 28, it passes through the main housing 5 of the cartridge via the plunger cutout 8 adjacent to each cartridge 1. The cross-shaped element 100 ensures that the plunger rod 42 will be axially aligned with the target drug cartridge 1. On further travel, the plunger rod 42 then enters the target cartridge 1 and contacts the cartridge stopper 3. The plunger rod 42 will continue to advance forward and will begin to drive the cartridge stopper 3 into the cartridge 1( Figure 19 and Figure 21 ), thereby discharging its contents into the cannula 13 that pierces its septum 2, into the cartridge top manifold 12, into the infusion set 16, and into the patient's body. Once the contents of the cartridge 1 have been completely discharged, the encoder motor 40 will then reverse to retract the plunger rod 42 to its initial position. Once at the initial position, the plunger rod 42 will retract to allow radial adjustment of the cross-shaped element 100 when aligning another cartridge 1 axially with the plunger rod 42. The cross-shaped element 100 can be rotated to align the individual cartridges 1 in any order, including allowing partial dispensing of a cartridge 1 (e.g., partial dispensing of cartridge A, then (full or partial) dispensing of cartridge B, then returning to cartridge A for further dispensing). In an embodiment, the rigid plunger rod 42 can be replaced with a flexible plunger rod or a telescoping plunger rod. Similarly, the device driving the plunger rod 42 can be replaced with a linear actuator, a pneumatic system, a magnetic system, or a spring-based system. One or more guides 44 can be provided for maintaining the alignment of the plunger rod 42, including being supported separately from the cartridge barrel 28 to be fixed relative to the cartridge barrel, as Figure 20 and Figure 21 shown.

[0038] In one embodiment, any of the combination drug delivery devices disclosed herein is capable of delivering two or more drugs to benefit a patient suffering from any one of a wide variety of diseases or conditions (e.g., cancer, autoimmune disorders, inflammatory disorders, cardiovascular diseases, or fibrotic disorders). In one embodiment, one or more of the cartridges in cartridge 1 may contain a single drug. In one embodiment, one or more of the cartridges in cartridge 1 may contain two or more co-formulated drugs. In one embodiment, one or more of the cartridges in cartridge 1 may contain a drug in solid form (such as tablets, capsules, powders, lyophilized, dry spray) which may be reconstituted with a diluent flowing therein to form a liquid drug.

[0039] In one embodiment, one or more of the drugs of any of the combination drug delivery devices disclosed herein are immune checkpoint inhibitors. In certain embodiments, the immune checkpoint inhibitor is a programmed death-1 (“PD-1”) pathway inhibitor, a cytotoxic T-lymphocyte-associated antigen 4 (“CTLA-4”) antagonist, a lymphocyte activation gene-3 (“LAG3”) antagonist, a CD80 antagonist, a CD86 antagonist, a T cell immunoglobulin and mucin domain (“Tim-3”) antagonist, a T cell immunoreceptor with Ig and ITIM domains (“TIGIT”) antagonist, a CD20 antagonist, a CD96 antagonist, an indoleamine 2,3-dioxygenase (“IDO1”) antagonist, a stimulator of interferon genes (“STING”) antagonist, a GARP antagonist, a CD40 antagonist, an adenosine A2A receptor (“A2aR”) antagonist, a CEACAM1 (CD66a) antagonist, a CEA antagonist, a CD47 antagonist, a receptor-associated immunoglobulin domain-containing protein (“PVRIG”) antagonist, a tryptophan 2,3-dioxygenase (“TDO”) antagonist, a T cell activation V domain Ig inhibitor (“VISTA”) antagonist, or a killer cell immunoglobulin-like receptor (“KIR”) antagonist.

[0040] In one embodiment, the PD-1 pathway inhibitor is an anti-PD-1 antibody or an antigen-binding fragment thereof. In certain embodiments, the anti-PD-1 antibody is pembrolizumab (KEYTRUDA; MK-3475), pidilizumab (CT-011), nivolumab (OPDIVO; BMS-936558), PDR001, MEDI0680 (AMP-514), TSR-042, REGN2810, JS001, AMP-224 (GSK-2661380), PF-06801591, BGB-A317, BI 754091, or SHR-1210.

[0041] In one embodiment, the PD-1 pathway inhibitor is an anti-PD-L1 antibody or an antigen-binding fragment thereof. In certain embodiments, the anti-PD-L1 antibody is atezolizumab (TECENTRIQ; RG7446; MPDL3280A; RO5541267), durvalumab (MEDI4736), BMS-936559, avelumab (bavencio), LY3300054, CX-072 (Proclaim-CX-072), FAZ053, KN035, or MDX-1105.

[0042] 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 multi-potent killer T lymphocytes, autologous PD-1-targeted chimeric switch receptor-modified T lymphocytes, or PD-1 knockout autologous T lymphocytes.

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

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

[0045] In one embodiment, the immune checkpoint inhibitor is a CTLA-4 antagonist. In certain embodiments, the CTLA-4 antagonist is an anti-CTLA-4 antibody or an antigen-binding fragment thereof. In some embodiments, the anti-CTLA-4 antibody is ipilimumab (YERVOY), tremelimumab (ticilimumab; CP-675,206), AGEN-1884, or ATOR-1015. In one embodiment, any combination drug delivery device disclosed herein comprises a CTLA-4 antagonist, such as ipilimumab (YERVOY); and a PD-1 pathway inhibitor, such as nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA).

[0046] In one embodiment, the immune checkpoint inhibitor is an antagonist of LAG3. In certain embodiments, the LAG3 antagonist is an anti-LAG3 antibody or an antigen-binding fragment thereof. In certain embodiments, the anti-LAG3 antibody is relatlimab (BMS-986016), MK-4280 (28G-10), REGN3767, GSK2831781, IMP731 (H5L7BW), BAP050, IMP-701 (LAG-5250), IMP321, TSR-033, LAG525, BI 754111, or FS-118. In one embodiment, any of the combination drug delivery devices disclosed herein includes a LAG3 antagonist, such as relatlimab or MK-4280; and a PD-1 pathway inhibitor, such as nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA). In one embodiment, any of the combination drug delivery devices disclosed herein includes a LAG3 antagonist, such as relatlimab or MK-4280; and a CTLA-4 antagonist, such as ipilimumab (YERVOY). In one embodiment, any of the combination drug delivery devices disclosed herein includes a LAG3 antagonist, such as relatlimab or MK-4280; a CTLA-4 antagonist, such as ipilimumab (YERVOY); and a PD-1 pathway inhibitor, such as nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA).

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

[0048] In one embodiment, the immune checkpoint inhibitor is a TIGIT antagonist. In one embodiment, the TIGIT antagonist is an anti-TIGIT antibody or an antigen-binding fragment thereof. In certain embodiments, the anti-TIGIT antibody is BMS-986207, AB 154, COM902 (CGEN-15137), or OMP-313M32.

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

[0050] In one embodiment, the immune checkpoint inhibitor is an IDO1 antagonist. In another embodiment, 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 embodiment, the immune checkpoint inhibitor is a STING antagonist. In certain embodiments, the STING antagonist is a 2' or 3'-monofluoro-substituted cyclic dinucleotide; a 2'3'-difluoro-substituted mixed-bond 2',5'–3',5' cyclic dinucleotide; a 2'-fluoro-substituted bis-3',5' cyclic dinucleotide; a 2',2”-diF-Rp,Rp, bis-3',5' cyclic dinucleotide; or a fluorinated cyclic dinucleotide.

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

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

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

[0055] In one embodiment, the immune checkpoint inhibitor is a CD40 antagonist. In certain embodiments, the CD40 antagonist is an anti-CD40 antibody directed to its antigen-binding fragment. 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 soluble CD40 ligand (CD40-L). In one embodiment, the soluble CD40 ligand is a fusion polypeptide. In one embodiment, the soluble CD40 ligand is CD40-L / FC2 or monomeric CD40-L.

[0056] 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, itradefylline (KW-6002), preladenant (SCH420814), tozadenant (SYN115), vipadenant (BIIB014), HTL-1071, ST1535, SCH412348, SCH442416, SCH58261, ZM241385, or AZD4635.

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

[0058] In one embodiment, the immune checkpoint inhibitor is a CEA antagonist. In one embodiment, the CEA antagonist is an anti-CEA antibody or its antigen-binding fragment. In certain embodiments, the anti-CEA antibody is cergutuzumab amunaleukin (RG7813, RO-6895882) or RG7802 (RO6958688).

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

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

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

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

[0063] In one embodiment, one or more of the drugs in any of the combination drug delivery devices disclosed herein are immune checkpoint enhancers or stimulants.

[0064] In one embodiment, the immune checkpoint enhancer or stimulant 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 embodiment, the immune checkpoint enhancer or stimulator is an OX40 agonist. In certain embodiments, the OX40 agonist is an anti-OX40 antibody or an antigen-binding fragment thereof. In some embodiments, the anti-OX40 antibody is tavolixizumab (MEDI-0562), pogalizumab (MOXR0916, RG7888), GSK3174998, ATOR-1015, MEDI-6383, MEDI-6469, BMS 986178, PF-04518600 or RG7888 (MOXR0916). In another embodiment, the OX40 agonist is a cell-based therapy. In certain embodiments, the OX40 agonist is GINAKIT cells (iC9-GD2-CD28-OX40-expressing T lymphocytes).

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

[0067] 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 an 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 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 mAbRNA / GITRL RNA-transfected autologous dendritic cell vaccine or a GITRL RNA-transfected autologous dendritic cell vaccine.

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

[0069] In one embodiment, the immune checkpoint enhancer or stimulator is a CD80 agonist or a CD86 agonist. In some embodiments, the CD80 agonist or CD86 agonist is 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 CD86 agonist is a cell-based therapy. In one embodiment, the cell-based therapy is MGN1601 (allogeneic renal cell carcinoma vaccine).

[0070] In one embodiment, the immune checkpoint enhancer or stimulator is a CD28 agonist. In some embodiments, the CD28 agonist is an anti-CD28 antibody or an antigen-binding fragment thereof. In certain embodiments, the anti-CD28 antibody is TGN1412.

[0071] 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 lymphocytes); CD28CAR / CD137CAR-expressing T lymphocytes; allogeneic CD4+ memory Th1-like T cells / microparticle-bound anti-CD3 / anti-CD28; autologous T lymphocytes KTE-C19 transduced with anti-CD19 / CD28 / CD3zeta CARγ retroviral vector; autologous T lymphocytes transduced with anti-CEA IgCD28TCR; allogeneic T lymphocytes transduced with anti-EGFRvIIICAR; 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 co-stimulatory vaccine-elicited autologous T lymphocytes; or iC9-GD2-CD28-OX40-expressing T lymphocytes.

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

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

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

[0075] In one embodiment, one or more of the drugs in any of the combination drug delivery devices disclosed herein is an anti-CD73 antibody or an antigen-binding fragment thereof. In certain embodiments, the anti-CD73 antibody is MEDI9447.

[0076] In one embodiment, one or more of the drugs in any of the combination drug delivery devices disclosed herein is a TLR9 agonist. In one embodiment, the TLR9 agonist is agatolimod sodium.

[0077] In one embodiment, one or more of the drugs in any of the combination drug delivery devices disclosed herein is a cytokine. In certain embodiments, the cytokine is a member of the chemokine, interferon, interleukin, lymphokine, or tumor necrosis factor family. In some embodiments, the cytokine is IL-2, IL-15, or interferon-γ.

[0078] In one embodiment, one or more of the drugs in any of the combination 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-β-2; autologous HPV-16 / 18 E6 / E7-specific TGF-β-resistant T lymphocytes; or TGF-β-resistant LMP-specific cytotoxic T lymphocytes.

[0079] In one embodiment, one or more of the drugs in any of the combination drug delivery devices disclosed herein is an iNOS antagonist. In some embodiments, the iNOS antagonist is N-acetylcysteine (NAC), aminoguanidine, L-NAME, or S,S-1,4-phenylene-bis(1,2-ethylenediyl)bis-isothiourea).

[0080] In one embodiment, one or more of the drugs in any of the combination drug delivery devices disclosed herein are SHP-1 antagonists.

[0081] In one embodiment, one or more of the drugs in any of the combination drug delivery devices disclosed herein are colony stimulating factor 1 receptor (“CSF1R”) antagonists. In certain embodiments, the CSF1R antagonist is an anti-CSF1R antibody or an antigen-binding fragment thereof. In some embodiments, the anti-CSF1R antibody is emactuzumab.

[0082] In one embodiment, one or more of the drugs in any of the combination drug delivery devices disclosed herein are agonists of TNF family members. In some embodiments, the agonist of TNF family members is ATOR 1016, ABBV-621 or adalimumab.

[0083] In one embodiment, one or more of the drugs in any of the combination drug delivery devices disclosed herein is interleukin 2 (IL-2), such as aldesleukin. Preferably, IL-2 or conjugated IL-2 (e.g., polyethylene glycolated) has been modified to selectively activate T effector cells relative to T regulatory cells (“T-eff IL-2”), such as bempegaldesleukin. In one embodiment, any of the combination drug delivery devices disclosed herein includes a modified IL-2 that selectively activates T effector cells relative to T regulatory cells, such as bempegaldesleukin; and a PD-1 pathway inhibitor, such as nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA). In one embodiment, any of the combination drug delivery devices disclosed herein includes a modified IL-2 that selectively activates T effector cells relative to T regulatory cells, such as bempegaldesleukin; and a LAG3 antagonist, such as relatlimab or MK-4280. In one embodiment, any of the combination drug delivery devices disclosed herein includes a modified IL-2 that selectively activates T effector cells relative to T regulatory cells, such as bempegaldesleukin; a PD-1 pathway inhibitor, such as nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA); and a LAG3 antagonist, such as relatlimab or MK-4280. In one embodiment, any of the combination drug delivery devices disclosed herein includes a modified IL-2 that selectively activates T effector cells relative to T regulatory cells, such as bempegaldesleukin; and a CTLA-4 antagonist, such as ipilimumab (YERVOY). In one embodiment, any of the combination drug delivery devices disclosed herein includes a modified IL-2 that selectively activates T effector cells relative to T regulatory cells, such as bempegaldesleukin; a PD-1 pathway inhibitor, such as nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA); and a CTLA-4 antagonist, such as ipilimumab (YERVOY). In one embodiment, any of the combination drug delivery devices disclosed herein includes a modified IL-2 that selectively activates T effector cells relative to T regulatory cells, such as bempegaldesleukin; a CTLA-4 antagonist, such as ipilimumab (YERVOY); and a LAG3 antagonist, such as relatlimab or MK-4280. In one embodiment, any of the combination drug delivery devices disclosed herein includes a modified IL-2 that selectively activates T effector cells relative to T regulatory cells, such as bempegaldesleukin; a PD-1 pathway inhibitor, such as nivolumab (OPDIVO) or pembrolizumab (KEYTRUDA); a CTLA-4 antagonist, such as ipilimumab (YERVOY); and a LAG3 antagonist, such as relatlimab or MK-4280.

[0084] In one embodiment, one or more of the drugs of any of the combination drug delivery devices disclosed herein is a CD160 (NK1) agonist. In certain embodiments, the CD160 (NK1) agonist is an anti-CD160 antibody or an antigen-binding fragment thereof. In one embodiment, the anti-CD160 antibody is BY55.

[0085] In one embodiment, one or more of the cartridges in cartridge 1 can contain a soluble CTLA-4 polypeptide, which can be used to treat, for example, T cell-mediated autoimmune diseases 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 in cartridge 1 of the combination drug delivery device as described herein includes a soluble CTLA-4 polypeptide, such as abatacept (ORENCIA); and a Bruton's tyrosine kinase inhibitor, such as branebrutinib. In certain embodiments, one or more of the cartridges in cartridge 1 of the combination drug delivery device as described herein includes a soluble CTLA-4 polypeptide, such as abatacept (ORENCIA); and a tyrosine kinase-2 inhibitor, such as BMS-986165. In certain embodiments, one or more of the cartridges in cartridge 1 of the combination drug delivery device as described herein includes a soluble CTLA-4 polypeptide, such as abatacept (ORENCIA); and interleukin-2 (IL-2) or "T-reg IL-2" that selectively activates T regulatory cells relative to T effector cell controls, such as BMS-986326 and NKTR-358.

Claims

1. A drug delivery device for delivering drugs from a plurality of drug cartridges to a patient, each of the drug cartridges including an elongated body and a stopper located in the body, the elongated body having a first end sealed with a septum and a second open end, wherein, In an initial state, each of the drug cartridges in the drug cartridge pack includes at least one drug contained in the body between its stopper and the septum, and the drug delivery device includes: a cylindrical cartridge configured to receive the plurality of drug cartridges; a reversibly axially movable plunger; a first shaft having a cross-shaped element mounted thereto, the first shaft being coupled to the cartridge such that rotation of the cross-shaped element causes corresponding rotation of the cartridge to align the plurality of drug cartridges individually with the plunger, the plunger being axially movable to urge the stopper of the aligned drug cartridge against the septum of the aligned drug cartridge, wherein the cross-shaped element includes a plurality of vanes separated by slots, each of the vanes radiating outwardly from the center of the cross-shaped element to an exposed free end, the free ends of the vanes together defining a discontinuous outer edge of the cross-shaped element surrounding the first shaft; and a reversibly rotatable drive member mounted to a second shaft for rotation therewith about a drive axis of rotation, the drive member including a first end surface facing generally in a direction parallel to the drive axis of rotation, a drive pin projecting from the first end surface in a first direction generally parallel to the drive axis of rotation, a second end surface offset from the first end surface in the first direction, and a side wall defined about the circumference of the drive member at a height between the first end surface and the second end surface, wherein the drive member is positioned such that the side wall is facing-aligned with the outer edge of the cross-shaped element, and wherein, as the drive member rotates about the drive axis of rotation, the drive pin traverses an arc, in a case where the drive pin traverses a first portion of the arc, the drive pin is received in a first slot of the slots of the cross-shaped element, in a case where the drive pin traverses a second portion of the arc, the drive pin bears against a first vane adjacent the first slot of the vanes, thereby generating a moment about the first shaft, which causes rotation of the cartridge, and in a case where the drive pin traverses a third portion of the arc, the drive pin stops bearing against the first vane and exits the first slot.

2. The drug delivery device according to claim 1, wherein, In a case where the drive pin traverses the third portion of the arc, a first portion of the side wall form-fittingly engages the free end of a second vane adjacent the first slot of the vanes to resist rotation of the cross-shaped element.

3. The drug delivery device according to claim 2, wherein, The first portion of the side wall extends about the drive member between spaced-apart points on the first end surface.

4. The drug delivery device according to claim 3, wherein, A second portion of the side wall extends continuously along a portion of the first end surface, and wherein the second portion of the side wall is spaced from the drive pin to allow the first vane to overlap the first end surface in a case where the drive pin traverses the second portion of the arc.

5. The drug delivery device according to claim 2, wherein, The first portion of the side wall is convex and the free end of the second vane is concave.

6. The drug delivery device according to claim 1, wherein, The second part of the side wall extends continuously along a part of the first end surface, and wherein the second part of the side wall is spaced apart from the drive pin to allow the first vane to overlap the first end surface when the drive pin traverses the second part of the arc.

7. The drug delivery device according to claim 1, wherein, The number of the vanes is equal to the number of the plurality of drug cartridges.

8. The drug delivery device according to claim 1, wherein The vanes are each formed similarly.

9. The drug delivery device according to claim 1, wherein When the drive pin traverses the first part, the second part, and the third part of the arc, the cartridge is rotated to radially displace a first drug cartridge of the plurality of drug cartridges out of alignment with the plunger and to align a second drug cartridge of the plurality of drug cartridges with the plunger, the second drug cartridge being directly adjacent to the first drug cartridge.

10. The drug delivery device according to claim 1, wherein, Within one rotation of the drive pin about the drive rotation axis, the drive pin traverses the first part, the second part, and the third part of the arc.

11. The drug delivery device according to claim 1, further comprising an electric motor for rotating the second shaft about the drive rotation axis.

12. The drug delivery device according to claim 1, wherein, The first shaft and the second shaft are generally parallel.

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

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

15. The drug delivery device according to claim 13, further comprising a plurality of fluid channels individually connected to the plurality of cannulas.

16. The drug delivery device according to claim 15, wherein, The plurality of fluid channels converge to a common outlet.

17. The drug delivery device according to claim 13, wherein, The plunger urges 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 discharged through the cannula piercing the septum of the aligned drug cartridge.

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