Cell avidity analysis apparatus

Abstract

The invention is directed to Cell avidity analysis apparatus (100). The apparatus comprises a housing (110) for housing components of the apparatus (100). The apparatus comprises a centrifuge unit (200) located inside the housing (110). The centrifuge unit (200) is arranged for holding and centrifuging a sample holder (802), preferably a sample holder (802) held within a substantially hermetically sealed casing (803). The apparatus also comprises an imaging device (300), preferably a microscopy device, for imaging at least a first section of the sample holder (802), preferably said first section being formed by a section of a flow channel (851, 852, 853) of said sample holder (802). The imaging device (300) is located inside the housing (110) and outside the centrifuge unit (200). The apparatus (100) further comprises a handling system (400) located inside the housing (110). The handling system (400) is arranged for placing the sample holder (802) inside the centrifuge (200) and / or arranged for taking the sample holder (802) out of the centrifuge (200) and towards the imaging device (300).

Description

[0001] Title: Cell avidity analysis apparatus

[0002] TECHNICAL FIELD

[0003] The invention relates to a cell avidity analysis device.

[0004] BACKGROUND

[0005] In cell avidity analysis, which for instance may be performed to facilitate cell therapy drug development, the overall cellular binding strength, i.e. the cell avidity, is often analysed in vitro by applying a force to bound cells, e.g. effector cells bound to target cells. An in vitro cell avidity analysis may for example be performed in order to provide a relatively relevant prediction reflecting an in vivo interaction between effector cells, for instance T cells, and target cells, in particular target antigens or immune cells. It will be appreciated that analysing the cell avidity for different effector cells, which are provided with different candidate receptors, can allow one to compare different effector cells. Implementing cell avidity analysis at a relatively early stage of cell therapy drug development may thus facilitate relatively early identification of relatively good lead candidates, which thereby may accelerate the development process and / or make the development more time and / or cost effective.

[0006] In cell avidity analysis processes, control over fluids and cells to be analysed and / or control over interaction and / or incubation time may be of high importance. For example, in order to obtain reproducible results, it may be important to tightly control incubation time and / or other parameters. Known methods for handling samples usually tend to require elaborate manipulation, in particular in manners requiring relatively much manual labour.

[0007] Cell avidity analyses may predict cellular responses relatively well, and may drive relatively good and / or relatively well informed decisions at relatively early stages of drug selection and may improve clinical outcomes. And, although there are already processes and devices to perform cell avidity analysis, there still is a desire for devices and / or methods for further improving cell avidity analysis.

[0008] It is an object of the present invention to provide a novel cell avidity analysis device, in particular one wherein samples can be analysed relatively precisely and / or wherein multiple, preferably relatively many, samples can be analysed simultaneously and / or in relative hight throughput format. SUMMARY OF THE INVENTION

[0009] The present disclosure provides for a new and improved device for cell avidity analysis.

[0010] In particular, the present invention provides for a cell avidity analysis apparatus according to claim 1 .

[0011] In a first aspect, the cell avidity analysis apparatus comprises a housing for housing multiple components of the apparatus. The apparatus comprises a centrifuge unit located inside the housing, which may also be referred to as a so-called enclosure. Said centrifuge unit being arranged for holding and centrifuging a sample holder, preferably a sample holder held within a substantially hermetically sealed casing. The apparatus further comprises an imaging device, preferably a microscopy device, for imaging at least a first section of the sample holder, preferably said first section being formed by a section of a flow channel of said sample holder. Said imaging device is located inside the housing and outside the centrifuge unit. Further, the apparatus comprises a handling system located inside the housing. The handling system is arranged for placing the sample holder inside the centrifuge and / or arranged for taking the sample holder out of the centrifuge and bringing it towards the imaging device. For instance, the handling device may be arranged to place the sample holder on a first sample holder support for supporting the sample holder when the imaging device is imaging at least a first section of the sample holder.

[0012] By providing an apparatus in which both a centrifuge unit and an imaging device is provided, as well as a handling device which can bring a sample holder from the centrifuge unit towards the imaging device and / or vice versa, a cell avidity analysis device can be provided which as a single device can be used for centrifugation and imaging, in particular microscopy. By allowing the handling system to place the sample holder in the centrifuge unit, it can be enabled that the centrifuge unit can start operating at the exact intended moment. As a result, samples may be analysed relatively precisely. Besides, samples may be analysed in relative high throughput format.

[0013] By providing the imaging device outside of the centrifuge unit, the imaging device does not need to spin together with sample holder, which may make the apparatus less complex and / or relatively reliable / durable. It has-been found that imaging samples only after the centrifuging action has performed and the sample holder has already been removed from the centrifuge unit can provide for relatively good predictions reflecting an in vivo interaction between effector cells, for instance T cells, and target cells, in particular target antigens or immune cells. Surprisingly, it has been found that in order to for instance select an amount of different types of candidate effector cells (each type provided with a respective one of different types of receptors) out of a larger number of different types of effector cells, it is not necessary to know, for all those different types of effector cells, what the progression over time is of how many cells become unbound from target cells. It has been found that for making such selection, it is not necessary to exactly know at what magnitude of a force that increase over time and is applied to the bound cells those cells unbind and neither to exactly know after what amount of time that a certain force has been applied the cells unbind. Insofar the different types of effector cells have been subjected to the substantially same set of forces, one can afterwards, outside the centrifuge unit, look at a respective sample holder to see how many of the initially bound cells held thereby are still bound and / or how many have become detached due to the forces applied by means of the centrifuge unit. It has surprisingly been found that with only comparing images from before and after the centrifuging action, and thus without having any images made during the centrifuging action, different types of effector cells can be compared relatively well so that this can facilitate relatively early identification of relatively good lead effector cell candidates.

[0014] The cell avidity analysis apparatus of the present disclosure can thus make cell therapy drug development more time effective and / or cost effective.

[0015] In preferred embodiments, the sample holder may be removably held within a casing, in particular a substantially hermetically sealed casing. Said casing, which may also be referred to as a so-called enclosure, may comprise one, but preferably multiple casing parts, such as for example at least two casing parts. The casing parts may be arranged to be substantially hermetically sealed to each other, in particular in a manner in which it can be opened and closed in a substantially hermetical sealed manner again. Alternatively, or additionally, a seal can be provided between the sample holder and a respective casing part. The sample holder may thus be part of a cassette, the casing of which may thus holds said sample holder. By arranging the apparatus, preferably its handling system, such that it can remove the sample holder from the casing, the apparatus can enable that the sample holder can be imagined, in particular by means of a microscope, in particular while it is temporarily outside of the casing. On the other hand, the sample holder can be safely locked within the casing, for example during centrifuging and / or during incubation when receptor cells and effector cells can bind to each other. Keeping the sample holder, and thus a sample held by said sample holder, substantially hermetically locked within the cassette may for example counteract that the sample can become contaminated. Alternatively, or additionally, it may counteract that sample cells, in particular target cells, may unintentionally spread outside of the sample holder and / or outside of the cassette. For example, the sealing may counteract evaporation of a liquid held in a respective flow channel, for example during incubation. As another example, the sealing may counteract the forming of aerosols, for instance during centrifugation. As yet another example, the sealing may counteract spilling of sample material, for instance biological sample material, when one accidently drops the cassette.

[0016] The sample holder may comprise at least one flow channel, which may also be referred to as a so-called well. Preferably, the sample holder may comprise multiple flow channels, each of which may extend between a respective channel inlet and a respective channel outlet.

[0017] The apparatus may, for instance in such embodiments, then also comprise a loading station, located inside the housing, wherein the loading station is provided with a second sample holder support for holding the sample holder, which for instance may be present in an opened casing or part of said casing, more preferably a casing of which a second casing part, which may form a lid of the casing, has been temporarily removed. It will be appreciated that a sample holder held by said second sample holder may then also be completely removed from the cassette, if any. The handling system may be arranged to place the sample holder in, on and / or against the second sample holder support and / or to remove it therefrom, for instance in order to bring it towards a storage rack or the like, which may be provided inside an incubation station, which preferably can be located also inside the housing of the cell avidity analysis apparatus.

[0018] The loading station may then further be provided with at least one liquid handling module, such as for example a pipetting robot. Said liquid handling module can then be arranged for loading a liquid into at least one of the one or multiple flow channels of the sample holder. Preferably, said liquid handling module can then be arranged for loading a liquid into multiple flow channels of a 96-well, 384-well or 1536-well microplate conforming to the ANSI SLAS standards.

[0019] In preferred embodiments, the liquid handling module may comprise at least one set including a liquid dispenser for liquid insertion into the flow channel and a liquid remover for liquid removal from said flow channel. For example, both the liquid dispenser and the liquid remover may be formed by a tip or a respective pipette. Since, for example due to the size of the sample holder, the distal end of a pipette for letting liquid into the pipette and / or out of the pipette may be formed as a needle, such configuration may, at least in embodiments, be considered to be a so-called double needle configuration.

[0020] Preferably, the loading station may be arranged to load liquid into multiple ones of multiple flow channels of the sample holder at least partly simultaneously, such as for example enabling loading at least four, at least eight or at least sixteen flow channels at least partly simultaneously. For example therefore, the liquid handling module may comprise multiple liquid dispensers, preferably wherein each liquid dispenser is part of a set also comprising a respective liquid remover.

[0021] It is noted that the liquid handling module may comprise multiple sets each comprising a liquid dispenser, for instance in the form of a pipette, in particular an electronic pipette, and further comprising a liquid remover, for instance in the form of a pipette, in particular an electronic pipette.

[0022] Advantageously, the liquid handling module may be arranged such that said liquid dispenser can dispense into the channel inlet while said liquid remover simultaneously aspirates from the channel outlet of the same flow channel. This may for example facilitate achieving a relatively constant flow and / or facilitate counteracting overflow or emptying of said flow channel.

[0023] By providing the cell avidity analysis apparatus with an integrated loading station, the apparatus, which even without such loading station may already be considered to form more or less a full “lab-in-a box”, may be even more complete. The apparatus may for example be used by researchers to conduct cell avidity analysis outside of a traditional lab. In particular, the apparatus, which may thus be a so-called lab-in-a-box, may be in the form of a self-contained apparatus. It may, at least in embodiments, for example allow users to conduct cell avidity analysis substantially without needing further tools or lab equipment.

[0024] It will be appreciated that such a configuration may for example facilitate a relatively precise and / or relatively accurate loading of the sample holder(s). In addition, or alternatively, it may facilitate that the apparatus can work relatively autonomously. For example, the apparatus may at least in embodiments be arranged such that it can itself prepare the samples for the cell avidity analysis.

[0025] It is noted that the apparatus, which at least in embodiments may thus be considered to form more or less a full “lab-in-a box”, may be dimensioned such that it is relatively small compared to a lab room. For example, the apparatus may be dimensioned such that it is small enough to fit in a space of 2.2 m x 2.2 m x 2.2 m, preferably within a space of 2 m x 2 m x 2 m, more preferably within a space of 1 .8 m 1.8. m x 1.8 m, yet more preferably within a space of 1.6 m x 1.6 m x 1.6.

[0026] In particular, the cell avidity analysis apparatus may be dimensioned to serve as a tabletop device, or a so-called benchtop apparatus. This is, in embodiments the apparatus may thus be small and compact enough to be placed and used on a standard table or desk or benchtop, as opposed to large, industrial-sized equipment.

[0027] With regard to the centrifuge unit, it is note that advantageously said centrifuge unit may comprise a rotor provided with multiple receptacles, each one of which is arranged for receiving and holding a sample holder, in particular a sample holder provided in a respective housing or encasing, wherein said receptacles being arranged equidistantly and / or rotationally symmetrically about the rotational axis of the rotor. During centrifuging, the receptacles, which are mounted to the rotor, can rotate together with the rotor about the central axis of said rotor.

[0028] Preferably, each receptacle can be mounted with respect to the rotor, in a manner that enables it to hinge or swing about a hinging axis, said hinging axis extending transverse to the rotational axis of the rotor and more preferably substantially tangential to a virtual circle surrounding said rotor. In particular, as the central axis of the rotor may preferably extend vertically, the hinging axis may extend horizontally. Hence, it can be enabled that the sample holder can be loaded into the centrifuge unit in a first position, in particular a first position in which its one or more flow channels and / or substantially the entire sample holder extend(s) substantially horizontally, and can later on, in particular due to the centrifugal force caused by the centrifuging, be brought into a second position, in particular one in which the one or more flow channels and / or substantially the entire sample holder can extend in more upright position, preferably in a substantially vertical position. This may enable the vector of the combined gravitational and centrifugal force, that is applied to the sample under test, to remain substantially perpendicular to the channel surfaces. The apparatus may preferably be arranged such that differences of the combined forces can remain below 60 degrees, preferably below 20 degrees, and more preferably below 10 degrees, with respect to the normal to the respective wall of the flow channel to which cells may be bound, in particular a wall forming the ceiling of the flow channel. It is noted that said respective surface may be considered to be a so-called “flow cell surface”.

[0029] For example in this way, the receptacle can thus be in the form of a so-called swinging bucket.

[0030] Preferably, each of the receptacles can comprise a tray or the like for receiving and holding the respective sample holder, and the centrifuge unit can be arranged such that, in a rest position of the centrifuge, i.e. a position or state in which the centrifuge is not spinning, said tray extends in a substantially flat or horizontal position, in particular to allow the flow channel(s) to extend substantially horizontally.

[0031] By spinning the centrifuge, the sample holder, preferably held in a respective receptacle, can then pivot about its hinging axis, preferably thereby bringing its one or multiple flow channels in a substantially upright position and / or a position substantially parallel to the rotational axis of the rotor of the centrifuge unit.

[0032] In advantageous embodiments, the receptacle and / or a sample unit (e.g. in the form of a cell avidity analysis cassette) comprising the sample holder which is to be held by said receptacle and which corresponds to said receptacle, for example with regards to its exterior shape and dimensions, which for example may correspond to the interior shape and dimensions of said receptacle, may be arranged such that the sample holder can be placed in only one positions or only in a certain amount, of for instance two, different positions. These one or multiple certain positions may preferably be a position or positions in which the one or more flow channels are substantially radially extending when said one or more flow channels are initially extending substantially horizontally and will pivot towards a more upright position extending substantially parallel to the substantially vertically extending rotational axis of the rotor of the centrifuge unit. For instance therefore, it may be counteracted that fluid present in a respective flow channel will be pushed to flow in a longitudinal direction of said respective flow channel during acceleration or deceleration. An advantage thereof may for example lay in that it can be counteracted that cells bound to a respective wall of the flow channel, for example to an upper wall forming the ceiling of the flow channel, may unintentionally be pulled loose. Additionally, or alternatively, an advantage may be that a part of the fluid, which may contain potentially hazardous substances, may be accidently pushed out of the flow channel.

[0033] By letting at least one of the receptacles hold a releasably received counterweight, preferably one substantially dimensioned and / or substantially shaped as the cassette and / or as the casing of the sample holder, it can be facilitated that the counterweight can be replaced relatively easily, for example to match the weight of a respective cassette to be centrifuged.

[0034] In embodiments, the apparatus may comprise an opening device arranged for opening a casing which houses the sample holder, wherein said opening device is located inside the housing of the apparatus. The opening device may then be arranged for receiving and engaging a first casing part of the casing, while the apparatus, for instance its handling system, is arranged for engaging a second casing part of the casing and removing the second casing part from the first casing part. In embodiments, the second sample holder support may for example be part of the opening device, and may in particular be a part of said opening device which enables that said opening device is arranged for receiving and engaging the first casing part.

[0035] Preferably, the opening device can further be provided with an opening mechanism for unlocking one or multiple locks or locking mechanisms of the cassette, if any, wherein said one or multiple locks or locking mechanisms are preferably for releasably locking the first casing part with respect to the second casing part.

[0036] For example, the opening mechanism can comprise at least one, and preferably at least three, such as for instance four, push elements, preferably push rods, for unlocking or disengaging a respective lock formed as a releasable snap lock.

[0037] Advantageously, the cell avidity analysis apparatus may also comprise one or more storage racks for storing at least a respective sample holder, preferably for storing at least one cassette comprising a casing and the sample holder housed within said casing, wherein said one or more storage racks are located inside the housing of the apparatus. Said one or more storage racks may be located in an incubation station.

[0038] The handling system may then be arranged to move the sample holder, preferably the cassette provided with said sample holder, from the storage rack and / or the incubation station to the loading station and / or the opening device, if any, which opening device may be part of the loading station. Additionally, or alternatively, the handling system may for example be arranged to move the sample holder, preferably the cassette provided with said sample holder, from the loading station and / or the opening device, if any, which opening device may be part of the loading station, to the storage rack and / or the incubation station.

[0039] In embodiments, the apparatus may comprise at least one of a heater, a cooler, a humidifier, a dehumidifier or a CO2 control system for adapting and / or controlling the temperature, the humidity and / or the CO2 level in at least a part or section of the apparatus, preferably for at least adapting and / or controlling the temperature the humidity and / or the CO2 level in a part or section in which the storage rack is provided, such as for example the incubation station, if any. By doing so, one or more parts of the process, such as for example the incubation, may for instance be controlled relative well.

[0040] Advantageously, the cell avidity analysis apparatus may comprise a non-transitory computer-readable medium with instructions encoded thereon, and one or multiple processors configured to, when executing the instructions, perform at least one or more steps of a cell avidity analysis method.

[0041] A first example of such a step may for example be inverting the sample holder, in particular by means of the handling system, from a starting position, such as an upside up position, of the sample holder into an inverted position, such as for example the upside down position of the sample holder. Another example of such step may be timing how long the sample holder is in its inverted position. Yet another example of such step may be that, once a predetermined period of time has lapsed while the sample holder is in its inverted position, the sample holder is re-inverted the sample holder, in particular by means of the handling system, from said inverted position of the sample back to the starting position of the sample holder. This may for example allow performing cellular avidity determining methods or steps thereof, in particular methods, and / or one multiple steps thereof, as described for example in WO 2023 / 232881 A1 and WO 2023 / 126488 A1 , each of which are considered to be included in the present disclosure by reference, in particular performing the method of claim 1 of WO 2023 / 232881 A1.

[0042] One or more of such and / or other examples of steps for which the instruction(s) may be encoded on the non-transitory computer-readable medium, and which may be performed by the cell avidity analysis apparatus may be that of:

[0043] A) opening the cassette, if any, and removing the sample holder from the cassette’s casing; and / or

[0044] B) placing the sample holder, in particular one removed from a respective casing, in, on and / or against the second sample holder support; and / or

[0045] C) introducing a fluid, in particular one with a predefined concentration of target cells, into at least one, and preferably into multiple ones, of the one or more flow channels of the sample holder, in particular by means of the liquid handling module, in particular while the sample holder is held by the second sample holder support; and / or

[0046] D) placing the sample holder back into the casing and closing the casing, in particular in a substantially hermitically sealed manner; and / or

[0047] E) inverting the sample holder, preferably one held within a casing, in particular inverting it by means of the handling system; and / or

[0048] F) placing the inverted sample holder, in particular an entire cassette, onto a storage rack and / or into a storage location, for example one formed in an incubation station, preferably one of which the temperature and / or humidity and / or CO2 level is controlled to at least a certain extent, thereby for example allowing the target cells to settle to a wall surface, in particular one formed by a ceiling, and attach thereto, in particular to form a monolayer; and / or;

[0049] G) removing the sample holder, in particular the cassette, from the storage location; and / or

[0050] H) reinverting the sample holder, in particular the entire cassette; and / or opening the cassette’s casing and taking the sample holder out of it; and / or

[0051] I) placing the sample holder, in particular one removed from a respective casing, in, on and / or against the second sample holder support, in particular in an un-inverted position, which can be considered its upright position; and / or J) introducing a fluid, in particular one with a predefined concentration of effector cells, into at least one, and preferably into multiple ones, of the one or more flow channels of the sample holder, in particular by means of the liquid handling module, in particular while the sample holder is held by the second sample holder support; and / or

[0052] K) placing the sample holder back into the casing and closing the casing, in particular in a substantially hermitically sealed manner; and / or

[0053] L) inverting the sample holder, preferably one held within a casing, in particular inverting it by means of the handling system; and / or

[0054] M) placing the inverted sample holder, in particular an entire cassette comprising said sample holder, into a storage location, for example one formed in an incubation station, preferably one of which the temperature and / or humidity and / or CO2 level is controlled to at least a certain extent, thereby for example allowing the effector cells to precipitate and to attach to the target cells attached to the ceiling; and / or

[0055] N) removing the sample holder, in particular the cassette, from the storage location; and / or

[0056] O) reinverting the sample holder, in particular the entire cassette; and / or

[0057] P) opening the cassette casing and taking the sample holder out of it; and / or

[0058] Q) placing the sample holder, in particular one removed from a respective casing, in, on and / or against the first sample holder support, preferably in the upright position of the sample holder; and / or

[0059] R) capturing, by means of the imaging device, an image of at least a first section of the sample holder, preferably said first section being formed by a section of the flow channel of said sample holder, in particular such as to capture an image of the effector cells; and / or

[0060] S) placing the sample holder back into the casing and closing the casing, in particular in a substantially hermitically sealed manner; and / or

[0061] T) placing the sample holder, in particular an entire cassette, into a receptacle of the centrifuge unit, in particular in an upright position of the sample holder; and / or

[0062] II) centrifuging the sample holder at a predefined centrifugal force, for example one of at least 10xG, preferably at least 50xG, such as for example at least 100xG, more preferably at least 500xG, such as for example substantially 1000xG, for a predefined amount of time, for example one of at least 10 seconds, more preferably one of at least 30 seconds, such as for example one of at least 120 seconds; and / or

[0063] V) removing the sample holder, in particular the cassette, from the centrifuge unit; and / or

[0064] W) opening the cassette’s casing and taking the sample holder out of it; and / or

[0065] X) placing the sample holder, in particular one removed from a respective casing, in, on and / or against the first sample holder support, preferably in the upright position of the sample holder; and / or

[0066] Y) capturing, by means of the imaging device, a second image of at least the first section of the sample holder, in particular such as to capture a second image of the effector cells still attached to the target cells, preferably wherein said second image is made within at most 10 minutes from the moment the centrifuging had stopped, more preferably within at most 5 minutes, such as for example within 3 minutes or within 120 seconds.

[0067] By comparing both images with respect to each other, the cell avidity can be analysed.

[0068] It will be appreciated that not all steps have to be performed, and that some or more of the steps may differ from the steps mentioned above. For example, the target cells, which may form a monolayer at the ceiling when the sample support is in its inverted state, may alternatively become attached to a different wall surface, for example a bottom wall. As another example, it may also be possible to provide a monolayer of effector cells, and let the target cells subsequently bind to such a monolayer of the effector cells.

[0069] Additionally, or alternatively, one or more other steps may be performed. For example, before introducing the effector cells to be bound to the target cells attached to the ceiling (or other wall), the sample holder may be centrifuged, for example in the upside-up position to loosen target cells not properly attached to the ceiling.

[0070] Additionally or alternatively, before introducing the effector cells, the liquid containing unbound target cells may be washed out of the flow channel, preferably by means of the liquid handling module.

[0071] Additionally or alternatively, before introducing the effector cells, for instance after optionally washing out the liquid containing the unbound target cells, it is also possible to capture an additional image of the monolayer, in particular in order to check the quality of said monolayer of target cells before introduction of the effector cells.

[0072] Additionally or alternatively, after introducing the effector cells to be bound to the target cells attached to the ceiling (or other wall), the sample holder may be centrifuged, for example in the upside-down position to accelerate the sedimentation of the effector cells onto the target cells. Advantageously, this may limit the spread in the sedimentation time of the effector cells thereby improving the control over the incubation time. For example in order to limit the spread in sedimentation time by facilitating an accelerated sedimentation by means centrifugation of the sample holder, which may be referred to as a form of spin-assisted cell settling (SACS), the cell avidity analysis apparatus may in embodiments be arranged for inverting, centrifuging and reinverting the sample holder, and for measuring and / or controlling the duration of centrifuging, and preferably for also measuring and / or controlling the time between inverting and reinverting and / or the time between inverting and centrifuging after reinverting the sample holder.

[0073] One or a multiple number of such and / or other steps may be executed by the cell avidity analysis apparatus, and the apparatus may be arranged to execute at least one of such steps. The non-transitory computer-readable medium, if any, may thus have instructions encoded thereon which correspond to one more of such steps and which may make that the one or multiple processors, if any, execute these one or multiple instructions to let the apparatus execute the respective step or steps.

[0074] It will be appreciated that use of the apparatus may comprise: providing the apparatus; providing the apparatus with a sample holder, in particular one held in a cassette casing; providing the apparatus with at least a first liquid, preferably one comprising target cells; and providing the apparatus with at least one second liquid, preferably one comprising effector cells, preferably multiple different second liquids. The use may then further comprise steps of centrifuging the sample holder inside the housing of the apparatus, preferably when said sample holder is held within the cassette’s casing, and a subsequent step of imaging the sample holder inside the housing of the apparatus, preferably after said sample holder has been removed from the cassette’s casing, more preferably inside the housing of the apparatus.

[0075] In embodiments, the non-transitory computer-readable medium, if any, may also contain instructions and / or models, such as deep learning models, for monolayer and / or effector cell detection or the like, which for example can be used to determine cell avidity parameters based on a comparison of a first image obtained before centrifugal force has been applied to a certain sample and a second image obtained after centrifugal force has been applied to said sample.

[0076] Other advantageous embodiments according to the invention are described in the following claims.

[0077] BRIEF DESCRIPTION OF THE DRAWINGS

[0078] By way of example only, embodiments of the present invention will now be described with reference to the accompanying schematic drawings in which:

[0079] Fig. 1 shows a schematical perspective view of an embodiment of a cell avidity analysis apparatus according to the present invention;

[0080] Fig. 2 shows a partly cut-away perspective view of said apparatus omitting for instance some cover parts of the housing in order enhance the visibility of respective components of the apparatus;

[0081] Fig. 3 shows a partly cut-away frontal view of the apparatus;

[0082] Fig. 4 shows a detail of a partly cut-away perspective view of the apparatus;

[0083] Fig. 5 shows a partly cut-away detail showing a loading station of the apparatus;

[0084] Fig. 6 shows a partly cut-away rear view of the apparatus;

[0085] Fig. 7 shows a partly cut-away detail showing a centrifuge unit of the apparatus;

[0086] Fig. 8 shows an exploded view of a cassette for use in the apparatus; and

[0087] Fig. 9 shows a schematical cross-sectional view of a detail of a sample holder of the cassette of Fig. 8.

[0088] DETAILED DESCRIPTION OF EMBODIMENTS

[0089] It is noted that the figures show merely a preferred embodiment according to the invention. In the figures, the same reference numbers and symbols refer to equal or corresponding parts.

[0090] The figures are intended for illustrative purposes only, and do not serve as restriction of the scope of the protection as laid down by the claims.

[0091] It will be readily understood that the components of the embodiments as generally described in the present disclosure and illustrated in the appended figures could be arranged and designed in a wide variety of different configurations. Thus, also the following more detailed description of various embodiments, as represented in the figures, is not intended to limit the scope of the present disclosure but is merely representative of various embodiments. While the various aspects of the embodiments are presented in drawings, the drawings are not necessarily drawn to scale unless specifically indicated.

[0092] The described embodiments are to be considered in all respects only as illustrative and not restrictive. The scope of the present disclosure is, therefore, indicated by the appended claims rather than by this detailed description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.

[0093] Reference throughout this specification to features, advantages, or similar language does not imply that all of the features and advantages that may be realized with the present disclosure should be or are in any single example of the present disclosure. Rather, language referring to the features and advantages is understood to mean that a specific feature, advantage, or characteristic described in connection with an embodiment is included in at least one embodiment of the present disclosure. Thus, discussions of the features and advantages, and similar language, throughout this specification may, but do not necessarily, refer to the same example.

[0094] Furthermore, the described features, advantages, and characteristics of the present disclosure may be combined in any suitable manner in one or more embodiments. One skilled in the relevant art will recognize, in light of the description herein, that the present disclosure may be practiced without one or more of the specific features or advantages of a particular embodiment. In other instances, additional features and advantages may be recognized in certain embodiments that may not be present in all embodiments of the present disclosure. Reference throughout this specification to "one embodiment", "an embodiment", “an exemplary embodiment”, or similar language means that a particular feature, structure, or characteristic described in connection with the indicated embodiment is included in at least one embodiment of the present disclosure. Thus, the phrases "in one embodiment", "in an embodiment", “in and exemplary embodiment” and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.

[0095] Fig. 1. shows an exemplary embodiment of a cell avidity analysis apparatus 100. The apparatus 100 comprises a housing 110 for housing components of the apparatus 100. The housing 110 may also be considered to be a so-called enclosure. The housing may comprise a frame and one or multiple cover parts for covering the interior of the apparatus.

[0096] Preferably, said housing 110 may be dimensioned such that the apparatus 100 can form a so-called benchtop apparatus. In particular, the housing 110 and / or the entire apparatus 100 may have dimensions such that neither one of its height H110, H100, depth D110, D100 and width W110, W100 extend 1 .8 meter, and preferably not extend 1.6 meter, more preferably not extend 1.5 m.

[0097] One of the components of the apparatus 100 is a centrifuge unit 200. The centrifuge unit 200 is located inside the housing 110, which can be seen for example in Fig.6, which shows a rear view of the apparatus 100. As is the case in the here shown embodiment, and as can be seen relatively well in Fig. 7, the centrifuge unit 200 may preferably be in the form a so-called swinging-bucket centrifuge, in particular a swinging-bucket centrifuge specifically arranged to receive the cassettes 801 described below.

[0098] The centrifuge unit 200 is arranged for holding and centrifuging a sample holder 802, preferably a sample holder 802 held within a substantially hermetically sealed casing 803. The centrifuge unit 200 can thus be arranged for holding and centrifuging a cell avidity analysis cassette 801 , an exemplary embodiment of which is shown in Fig. 8. As can be seen in Fig. 7, the centrifuge unit 200 may comprise its own housing 280, wherein this centrifuge housing may enclose the elements or components of said centrifuge unit 200.

[0099] The centrifuge unit 200 may comprise a rotor 210 provided with multiple receptacles 220, 230, which preferably are evenly balanced around a central axis 211 of the rotor, in particular by symmetrically arranging them around said central axis 211. Although the here shown embodiment has two of such receptacles, the centrifuge unit 200 may have another number of receptacles in other embodiments, such as for example three or four receptacles.

[0100] The receptacles can thus be positioned equidistantly and / or rotationally symmetrically about the rotational axis of the rotor 210.

[0101] Each receptacle 220, 230 can be arranged for receiving and holding a sample holder 802. For example the receptacle 220, 230 can be arranged for holding the sample 802, in particular a sample holder 802 held within a cassette’s casing 803. The receptacle 220, 230 may for example comprise a tray 221 , 231 which is arranged to receive and hold the cassette’s casing 803, preferably to securely hold it in a substantially form-fitting manner. Additionally or alternatively, the receptacle 220, 230 may be provided with means to securely hold the casing 803 and / or a sample holder 803, for example means which can enable to click it into place in a removable manner.

[0102] Preferably, each receptacle 220, 230 can be hingedly mounted with respect to the rotor 210 in order to enable to hinge or swing about a respective hinging axis A220, A230, in particular due to centrifugal action. The hinging axis A220, A230 may extend transverse to the rotational axis 211 of the rotor 210 and more preferably substantially tangential to a virtual circle surrounding said rotor 210.

[0103] As can be seen in Fig. 6 and Fig.7, each of the receptacles 220, 230 may comprise a tray 221 , 231 for receiving and holding the respective sample holder 802, which preferably may be part of a cassette 801. The centrifuge unit 200 can then be arranged such that, in a rest position of the centrifuge 200, which position is shown in Fig. 6 and Fig. 7, said tray 220, 230 extends in a substantially flat or horizontal position.

[0104] In particular to balance the weight, at least one of the receptacles can hold a counterweight, preferably a releasably received counterweight, more preferably one substantially dimensioned and / or substantially shaped as the casing 803 of the sample holder 802. This may facilitate that the counterweight may be replaced relatively easily, for example by loading a new one into the apparatus 100, for instance via an input door 111 , flap, tray, or the like, which may also be used to insert a cassette 801 comprising the sample holder 802 into the apparatus 100. This may for example be advantageous in case the design of the cassette 801 , which may be so-called consumable or so-called single use product or so-called disposable product, may change after some time, and / or in case multiple different cassettes are available, as this may thus enable that the counterweight may be changed, in a relatively convenient manner, to correspond with a respective cassette being used.

[0105] It is also possible that one or more counterweights, in particular substantially dimensioned and / or substantially shaped as the casing 803 of the cassette 801 , are stored inside the apparatus 100, and that a handling device 400 of the apparatus 100 can place a desired one, for example one with a desired weight or mass corresponding to the weigh or mass of a cassette 801 holding the sample(s) to be analysed. In this manner, the counterweight can for example easily be changed if necessary or desired. Although one or more counterweights may be provided, it is also possible that two or more cassettes 801 comprising at least a respective sample holder 802, or sample holders which are embodied in a different way, may be used and balance each other out, in particular then thus without using any dedicated counterweight.

[0106] The apparatus 100 further has an imaging device 300, preferably a microscopy device, for imaging at least a first section of the sample holder 802. As can be seen for example in Fig. 3 and Fig. 6, the imaging device 300 is located inside the housing 110, but outside the centrifuge unit 200.

[0107] Further, the apparatus 100 comprises a handling system 400. Said handling system 400 is also located inside the housing 100. The handling system 400 may comprise for instance a gripper 410, which may be arranged to releasably grip and hold the sample holder 802, in particular one removed from the casing 803 of a cassette 801. The gripper 410 may for example be an electric gripper and / or may comprise fingers for gripping and holding the sample holder 802. Further, the handling system 400 may comprise one or more transport systems 420, in particular to transport one or more grippers 410, which then may hold a cassette 801 and / or sample holder 802. The transport system may for example comprise a rack and pinion system, guiding rails, and / or one or more other parts.

[0108] It is noted that the handling system 400 is arranged for placing the sample holder 802 inside the centrifuge 200 and / or arranged for taking the sample holder 802 out of the centrifuge 200 and bringing it towards the imaging device 300.

[0109] As mentioned above, the imaging device 300 is for imaging at least a first section of the sample holder 802. Preferably, said first section can be formed by a section of a flow channel 851 , 852, 853 of said sample holder 802.

[0110] Fig. 8 shows the sample holder 802 as being part of the cassette 801. Preferably, as is the case in the here shown exemplary embodiment, the sample holder 802 can be in the form of a sample plate 820, which for example may be build up out of multiple components or parts 821 , 822.

[0111] Here, the sample holder 802 comprises multiple flow channels 851 , 852, 853, each extending between a respective channel inlet 851A, 852A, 853A and a respective channel outlet 851 B, 852B, 853B. All channel inlets 851 A, 852a, 853A and all channel outlets 851 B, 852B, 853B are preferably provided at the same side, in particular at the upper side 820A, of the sample plate 820. Although the here shown exemplary embodiment comprises forty eight flow channels 851 , 852, 853, alternative embodiments may have another number of flow channels, for example 192 or 768 channels, such that the combined number of inlets and outlets together may for example be 384 or 1536. By having a combined number of 96, 384 or 1536 inlets and outlets, the combined number of inlets and outlets may correspond to the number of wells of a 96-well, 384-well or a 1536-well microplate, preferably that of a 96-well, 384-well or 1536-well microplate conforming to the ANSI SLAS standards. It will be appreciated that the locations of the channel inlets and the locations of the channel outlets, when seen from above, may correspond to the locations of the wells of a so-called microplate, preferably that of a microplate conforming to the ANSI SLAS standards.

[0112] When seen from above, the multiple flow channels 851 , 852, 853 can thus be arranged in an array comprising for instance twelve columns of inlets and outlets, preferably wherein the distance between the virtual central axes of two adjacent columns, i.e. the distance between the virtual central axes 851A’ of an inlet 851A and an adjacent outlet, is 9 mm, 4.5 mm or 2.25 mm. Additionally, or alternatively, when seen from above, the array may also comprise multiple rows, for instance eight rows, preferably wherein the distance between the virtual central axes of two adjacent rows can be 9 mm, 4.5 mm or 2.25 mm, and preferably correspond to the distance between the virtual central axes of an inlet and an adjacent outlet.

[0113] In embodiments, dimensions, in particular outer dimensions, of the sample plate 820 may correspond to respective dimensions of the ANSI SLAS standards. For example, the dimensions of the sample plate 820 corresponding to respective dimensions of the ANSI SLAS standards may comprises one or multiple dimensions regarding the length of the footprint of the sample plate 820 and / or one or multiple dimensions regarding the width of the footprint of the sample plate 820.

[0114] As can be seen relatively well in Fig. 9, which shows a schematical cross-sectional view of a detail of the sample holder 802 of the cassette 801 of Fig. 8, the sample holder 802, which may preferably thus be in the form of a sample plate 820, can comprise a flat base plate 821 , for instance substantially made of COP (cyclic olefin polymer) or another suitable polymer, another suitable plastic, or any other suitable material. The sample holder 802 may further comprise one or multiple top parts 822 attached to the upper side of the flat base plate 821. Preferably, the top part 822 or top parts may be made substantially of the same material as the material of the base plate 821 , and may for example also be made at substantially of COP.

[0115] One or multiple regions 8211 of the upper side of the base plate 821 may form at least a part of a respective bottom of a respective one of the one or multiple flow channels 851. The top part 822 may then define at least part of a respective ceiling 8221 of a respective one of the multiple flow channels 851 , and may preferably also form at least part of the respective channel inlet 851A and at least part of the respective channel outlet 851 B.

[0116] The sample holder 802, at least below at least a part of the respective flow channel 851 , 852, 853 and / or at least above a part, of the respective flow channel 851 , 852, 853, and preferably both below and above the same part of the flow channel, may be transparent to predefined electromagnetic radiation, preferably light, more preferably visible light. This may facilitate imaging samples within the respective flow channel, for example by means of a microscope or other imaging device.

[0117] Actually, in embodiments, substantially the entire sample holder 2 may be made of substantially transparent material.

[0118] Further, at least a part of the ceiling 8221 , and preferably the entire ceiling 8221 , of the flow channel 851 may extend substantially parallel to at least a respective portion of an upper surface 8228 of the sample holder 802 located above said at least part of the ceiling 8221 and substantially parallel to at least a respective portion of a lower surface 8218 of the sample holder 802 located below said at least part of the ceiling 8221.

[0119] The sample holder 802 may define a first optical distance to be measured in a direction perpendicular to said at least part of the ceiling 8221 of the flow channel 851 , and which first optical distance is to be measured from said upper surface 8228 of the sample holder 802 to said ceiling 8221.

[0120] The sample holder 802, when the flow channel 852 is filled with an aqueous medium 8100, as is the case in Fig. 9 defines a second optical distance to be measured, in a direction perpendicular to said at least part of the ceiling 8221 of the flow channel 851 , from said lower surface 8218 to said ceiling 8221. The refractive index of the aqueous medium may be in the range of n = 1.20 to n = 1.46 or may be considered as n = 1.33 ±10%. Preferably, the refractive index of said aqueous medium may be about n = 1 .33.

[0121] It may be advantageous when said first optical distance substantially equals said second optical distance. This may for example enable that cells, or other sample material, present on or against said ceiling 8221 can relatively simply be observed from either the top side or the bottom side, for instance without substantially adjusting an imaging device or its optics, such as a microscope or the like.

[0122] It is noted that said first optical distance substantially equalling said second optical distance may be considered as that they do not differ more than 400 pm, preferably not more than 200 pm, yet more preferably not more than 100 pm.

[0123] The sample holder 802 may be provided with a least one first abutment surface for facilitating positioning the sample holder 802 with respect to an imaging device in a first position of the sample holder 802. For example, the first abutment surface may be formed by the upper surface 8228 of the top part 822 of the sample holder 802.

[0124] The sample holder 802 may further be provided with at least one second abutment surface 861 , 862, 863 for facilitating positioning the sample holder 802 with respect to the imaging device in a second position of the sample holder 802 which is an upside-down with respect to its first position. Said one or more second abutment surfaces 861 , 862, 863 may preferably be formed by one or multiple uncovered portions of the lower surface of said same top part 822. The base plate 821 may thereto be provided with recesses or the like, as can be seen in Fig. 8, which may enable that the lower side of the top part 822 can locally be left free. This is, at the locations of said one or multiple second abutment surfaces 861 , 862, 863, the top part 822 is locally not covered by the base plate 821. Preferably, this is done at at least three positions 861 , 862, 863, in particular ones which are located relative to each other in a triangular formation, thereby facilitating that the sample holder 892 can be supported relatively stable in its upside-down position by positioning it on said at least three positions positioned in a triangular shape.

[0125] Advantageously, both the first abutment surface and the one or multiple second abutment surfaces may thus be formed by respective surfaces of the same part, in particular by respective surfaces the top part 822. Since said top part 822 may define the wall 8221 which during an avidity experiment may be used to hold the cells thereto, and since it may be advantageous to for instance neatly control the distance from optical element of an imaging device to said wall 8221 , in particular to make relatively good images, it can be advantageous to use the top part 822 for providing the first and / or second abutments surfaces, preferably both the first and second abutment surfaces.

[0126] It is advantageous if least a part of the ceiling 8221 of the flow channel 851 is formed as a so-called functionalised wall surface 8221’. For instance, at least a part of the ceiling 8221 may thereto be provided with a functionalisation layer 8222. Preferably, the functionalised wall surface 8221’ can be arranged for facilitating the attachment of cells, such as for example target cells or effector cells, thereto. This may facilitate that the cells, in particular target cells can adhere to the ceiling 8221 .

[0127] It is also possible that at least a part of the ceiling of the flow channel 851 , 852, 853 is already provided with cellular objects, preferably biological cells, such as for example target cells.

[0128] Furthermore, at least a part of the bottom 8212 of the flow channel 851 , 852, 853 can at least partly be provided with an adhesion prevention layer 8213 or a so-called anti-fouling coating 8213, which may counteract that cellular objects, or at least certain cellular objects, may attach to at least said part of the bottom 8212. It is also possible that not only said part of the bottom or said bottom, but substantially all wall surfaces defining the flow channel but the functionalised wall surface 8221’, are provided with such an adhesion prevention layer 8213 or anti-fouling coating 8213.

[0129] It is noted that the cell avidity analysis cassette 801 does not only comprise the sample holder 802, but further also comprises a casing 803 for holding the sample holder 802 therewithin. The cassette 801 is arranged to hold the sample holder 802 in a substantially hermetically sealed manner within the casing 803.

[0130] Preferably, said casing 803 can be arranged to be substantially hermetically sealed, for example by means of a seal provided between a first casing part 831 and a second casing part 832.

[0131] Alternatively, or additionally, the cassette 801 can be arranged to provide one or multiple substantially hermetical sealings between the casing 803 and the sample holder 802. For example, an inner side of a casing part 832 to which the inlets and outlets face, may be provided with one or multiple seals, which may also counteract that there may be cross-contamination between different flow channels.

[0132] It is noted that the casing 803 is arranged to be opened, for instance to enable temporarily removing the sample holder 802 from the casing 8083 and / or to enable putting the sample holder 802 back into the casing 803. As such, the sample holder may for instance be positioned outside the casing 803 in order to make one or multiple images of at least a respective part of one or multiple samples provided in one or multiple respective flow channels.

[0133] It is noted that the casing 803 further is arranged to be closed again, in particular in a manner such that the cassette 801 holds the sample holder 802 again in the substantially hermetically sealed manner within the casing 803, when said sample holder 802 is placed back in case it had been temporarily removed from the casing 803 before.

[0134] The cassette 801 , preferably its casing 803, can provide protections against unauthorised access to the sample holder 802 held within the casing 803 to at least a certain extent. For example thereto, the cassette 801 , in particular its casing 803, may comprise one or multiple locks 804 or locking mechanisms 804, preferably internal locking mechanisms, for releasably locking the first casing part 831 with respect to the second casing part 832.

[0135] As can be seen in the exemplary embodiment shown in Fig. 8, the cassette 801 may comprise at least two, preferably at least three, more preferably at least four locks or locking mechanisms in the form of releasable snap locks 840, such as for instance so-called click fingers. Preferably, the multiple snap locks 840 can be positioned at such locations that it can be prevented, or at least complicated, that a person can click them all open simultaneously with one hand only.

[0136] In the here shown embodiment, each snap lock 840 comprises two engaging elements 841 , 842 for engaging each other in an interlocking manner, wherein one 841 of the two engaging elements is provided at, on and / or in the first casing part 831 and the other one 842 is provided at, on and / or in the second casing part 832. For example, one of the two engaging element 841 , 842 is formed as a protrusion (preferably in the form of a barb, which may comprise a stop / lock surface and a run- on surface) and the other formed as a corresponding recess (not shown), which may comprise a corresponding stop surface for engaging a stop surface or the like of said protrusion. One 841 of them, for instance the one formed as a protrusion, may be provided at, on or in a resilient element 8410, said resilient element for instance being in the form of a resilient arm or a resilient wall part. The resilient element 8410 may be arranged to be deflected in order to release the interlocking. Preferably, the snap lock 840, in particular its resilient element 8410, may be arranged for engagement by a respective tool, for instance by means of providing it with a respective anchor point 8411 or the like.

[0137] It is noted that the cassette 801 can be arranged such that, in a closed state of the casing 803, the casing 803, preferably the other one 832 of the two casing parts than the one 831 which is provided with the resilient element 8410, covers the resilient element 8410 to such an extent that it is at least substantially prevented that a barehanded person can deflect said resilient element 8410 to such extent that the interlocking can be released.

[0138] For example, the cassette 801 may be arranged such that, in a closed state of the casing 803, the casing 803, preferably by means of the other one 832 of the two casing parts than the one 831 which is provided with the resilient element 8410, covers the resilient element 8410 to such extent that it lets free only one or multiple areas 8310 having a respective width W310 and / or a respective height H8310 which not exceeds 1.5 cm, preferably not exceeding 12 mm, more preferably not exceeding 10 mm, yet more preferably not exceeding 8 mm. For example, the respective casing part 832, may thereto be provided with one or more openings 8320, in particular in the form of one or more recesses, which may keep only said one or multiple areas 8310 uncovered.

[0139] Advantageously, dimensions, in particular outer dimensions, of the casing 803 can correspond to respective dimensions of the ANSI SLAS standards. Preferably, said dimensions of the casing 803 corresponding to respective dimensions of the ANSI SLAS standards comprise at least one of: (i) one or multiple dimensions regarding the length L803 of the footprint of the casing 803; (ii) one or multiple dimensions regarding the width W803 of the footprint of the casing 803; and (iii) one or multiple dimensions regarding one or multiple flanges 830 of the casing 803, if any. Preferably, the one or multiple flanges, if any, is / are provided at the first casing part 831 , yet more preferably at a lower end of said first casing part 831.

[0140] As can be seen in Fig. 8, at least in embodiments, the outside of the casing 803, when seen from above, can be of a substantially rectangular design. Said substantially rectangular casing 803 may nevertheless not be entirely rotationally symmetrical about a virtual upstanding axis extending transverse to the footprint of the casing 803. For example, the casing 803 may be provided with a deviation 839, such as for instance a protrusion or indentation 839A. Preferably, as is the case in the here shown exemplary embodiment, the indentation 839A may be in the form of for instance a so-called corner notch 839A’, in particular one which is similar to the ones often present at corners of so-called microplates. Such or other deviation 839 can thus cause that the substantially rectangular casing is not rotationally symmetrical, when seen from above. This may for example help orienting the cassette 801 , the casing 803 and / or the sample holder 802.

[0141] Additionally, or alternatively, the first casing part 831 and the second casing part 832 may be arranged such that they only fit onto each other in one position, for instance by providing them with corresponding shapes which may include one or more corresponding protrusions and / or indentations. This may also apply to the sample holder, which in embodiments may also be provided with a such a deviation, in particular an indentation, more in particular a corner notch (which is not the case in the embodiment shown in Fig. 8).

[0142] In embodiments, the cassette 801 may be arranged such that the casing 803 can house the sample holder 802 in at least two positions, i.e. a first position in which the upper side 802A of the sample holder 802 faces up, as is the case in Fig. 8, and a second position in which the upper side 802A faces down, The cassette 801 may then be arranged such that it can hold the sample holder 802 in a substantially hermetically sealed manner within the casing 803 in both said first position and said second position.

[0143] As mentioned above, the cassette 801 can be used in the cell avidity analysis apparatus 100.

[0144] For example in order to allow the apparatus 100 to identify the cell avidity analysis cassette 801 and / or one or more samples held therein, said cassette 801 may be provided with at least one identification tag. The identification tag may for example be in the form of a transponder, more preferably in the form of a RFID tag, such as for example a UHF RFID tag.

[0145] The apparatus 100 may comprise one or multiple corresponding readers for reading the identification tag, such as one or multiple RFID readers. For example, the handling system 400 may be provided with at least one of the one or multiple tag readers, for instance at or near its gripper 410, if any. It is noted that the apparatus 100 may comprise a first sample holder support 501 for supporting the sample holder 802 when the imaging device 300 is imaging at least the first section of the sample holder 802. Said first sample holder support 501 is also located inside the housing 110.

[0146] The handling system 400 may be arranged for removing the sample holder 802, in particular when held in the casing 803, from the centrifuge unit 200 and placing the sample holder 802 at, on and / or in the first sample holder support 501. Preferably, the apparatus 100, in particular by way of its handling system 400, may be arranged to remove the sample holder 802 from the cassette’s casing 803 and put only the sample holder 802 at, on and / or in the first sample holder support 501 , for instance while holding or while having temporarily stored the casing 803 and / or one or more respective parts thereof.

[0147] It is noted that the first sample holder support 501 may be provided with a first stop surface or abutment against which the sample holder can rest. Said sample holder may further be provided with an opposing element arranged for applying pressure or force against the sample holder such as to press in against said first stop surface. For example, said opposing element may be driven, for example by an electric motor, to fix the sample holder in position on, in and / or at the support 501. Alternatively, said opposing element could for instance be biased towards the first stop surface by means of a spring load.

[0148] Additionally or alternatively, the first sample holder support 501 and the imaging device 300 may be movable with respect to each other, in particular in order to enable bringing a respective one of multiple sections of the sample holder 802, preferably multiple sections of multiple ones of multiple flow channels 851 , 852, 853 of the sample holder 802, into a field of view of the imaging device 300. For example, the first sample holder support 501 may then be movable by means of the handling system 400.

[0149] It will be appreciated that the apparatus 100, preferably its handling system 400, can thus be arranged for removing the sample holder 802 from the casing 803.

[0150] It is noted that the apparatus 100 may further comprise an opening device 600, which is located inside the housing 110 of the apparatus 100. The opening device 600 can for instance be seen in Fig. 2 and can even be better seen in Fig. 5. The opening device 600 is arranged for opening the casing 803 which houses the sample holder 802. In embodiments, as is the case in the exemplary embodiment shown in Fig. 5, the opening device 600 can be arranged for receiving and engaging a first casing part 831 of the casing 803, in particular the bottom part 831. The apparatus 100, preferably by means of its handling system 400, more preferably by means of a gripper 410 of said handling system 400, may be arranged for engaging a second casing part 832 of the casing 803 and removing the second casing part 832 from the first casing part 831 .

[0151] Advantageously, the opening device 600 can be provided with an opening mechanism 610 for unlocking one or multiple locks 804 or locking mechanisms 804, which the cassette 801 may comprise and which then may be for releasably locking the first casing part 831 with respect to the second casing part 832.

[0152] The opening mechanism 610 may for example comprise at least one, and preferably at least three, such as for instance four, push elements 611-614, preferably push rods or the like, for unlocking or disengaging a respective lock 804 formed as a releasable snap lock 840. Here, two 611 , 612 of the push elements are provided on a motorized frame 620 which pushes said two push elements 611 , 612 towards the other two 613, 614 such that all four push elements can engage a respective snap lock 840, in particular its resilient element 8410, more in particular at its respective anchor point 8411.

[0153] The apparatus 100 may comprise a loading station 700, located inside the housing 100, which partially 700’ can be seen for instance in Fig. 4 and Fig. 5. The loading station 700 can then be provided with a second sample holder support 701 for holding the sample holder 802, which for instance may be present in an opened casing 803 or part 831 of said casing, more preferably a casing 803 of which a second casing part 832, which may form a lid of the casing, has been temporarily removed.

[0154] In embodiments, the second sample holder support 701 may be part of the opening device 600, and may be a part thereof which enables that it is arranged for receiving and engaging the first casing part 831.

[0155] As can be seen relatively well in Fig. 4, the loading station 700 can further be provided with at least one liquid handling module 710, such as for example a pipetting robot, which is located inside the housing 110. Said liquid handling module 710 can be being arranged for loading a liquid into at least one of the one or multiple flow channels 851 , 852, 853 of the sample holder 802. Preferably, the loading station 710 can be arranged to load liquid into multiple ones of multiple flow channels 851 , 852, 853 of the sample holder 802 at least partly simultaneously. Preferably, the liquid handling module 710 can comprise sets 721 , 722 which each include a liquid dispenser 721 for liquid insertion into a respective flow channel and a liquid remover 722 for liquid removal from the same respective flow channel. In particular, the liquid handling module 710 is arranged such that said liquid dispenser 721 can dispense into the respective channel inlet 851A, 852A, 853A while said liquid remover of said same set simultaneously aspirates from the channel outlet 851 B, 852B, 853B of the same flow channel 851 , 852, 853, for example in particular to facilitate achieving a relatively constant flow and / or facilitate counteracting overflow or emptying of said flow channel. It is noted that although the example shown in Fig. 4 shows eight sets each having a dispenser and a corresponding remover, other embodiments may have other numbers of such sets, preferably a number corresponding to the numbers of rows of wells in a 96-well, 384-well or 1536-well microplate conforming to the ANSI SLAS standards. This is, the number of sets may for example be eight, sixteen or thirty two.

[0156] Further, as can be seen in Fig. 4 and in Fig. 5, the apparatus 100 may be arranged to hold liquid to be disposed in the channels of the sample holder 802. In particular, the apparatus and more in particular its loading station 700 may be arranged to transfer liquid from a respective container into the sample holder 802. For example, as can be seen in Figs. 4 and 5, the loading station 700 may be arranged to hold a well plate 730, in particular an ANSI SLAS well plate, preferably wherein the wells of said well plate hold liquid to be disposed into respective channels of the sample holder 802.

[0157] Furthermore, at least in embodiments, the apparatus 100 may comprise a cleaning station 750 for cleaning the liquid handling module 701 , or at least parts 721 , 722 thereof, for example at least part of the liquid dispensers 721 and liquid removers, which may for instance be in the form of pipettes or needles connected to a syringe. For example, the cleaning station 750 may be arranged for rinsing the inside of the needles or tips and preferably also for providing a washing solution, in particular in the form a cleaning liquid, around the outside of the needles or tips to be used for dispensing and / or removing sample liquids.

[0158] In embodiments, the handling system 400 may be arranged for turning the sample holder 802 upside down, for instance when said sample holder 802 is not located inside the casing 803, if any. However, advantageously, the handling system may, alternatively or additionally, be arranged to flip the entire cassette 801 upside down, for example in order to allow target cells to settle to the ceiling 8221 of the flow channel 851 , in particular to attach thereto such as to form a monolayer.

[0159] Moreover, the apparatus 100 may comprise one or more storage racks 910 for storing a sample holder 802, preferably for storing a respective cassette 801 comprising the casing 803 housing the sample holder 802 therewithin, wherein said one or more storage racks 901 are located inside the housing 110 of the apparatus.

[0160] The handling system 400 may then move the sample holder 802, preferably the cassette 801 provided with said sample holder 802, from the loading station 700 and / or the opening device 600, if any, which opening device may be part of the loading station, to the storage rack 910. For example, the apparatus 100, in particular its handling system 400, may invert the cassette 801 to an upside-down position before placing it in a respective storage rack 910.

[0161] The apparatus 100, in particular its handling system 400, may also be arranged to move the cassette 801 back from the storage rack 910 to the loading station 700 and / or the opening device 600, for instance after flipping it back to its upright position. As such, a second liquid for instance including effector cells, may then be introduced into the respective flow channel by means of the liquid handling module 710, for instance after the previous liquid, e.g. one containing unbound target cells, may be washed out of the flow channel, preferably by means of said liquid handling module 710.

[0162] It will be appreciated that the apparatus 100, in particular its handling system 400, may also be arranged to move the cassette between other components of said apparatus 100. For example, the handling system may be arranged to move the cassette 801 provided with said sample holder 802, from the loading station 700 and / or the opening device 600 to the first sample holder support 501 and / or vice versa. Alternatively or additionally, the handling system 400 may be arranged to move the cassette 801 from the centrifuge unit 200 to the first sample holder support 501 and / or vice versa. Alternatively or additionally, the handling system 400 may be arranged to move the cassette 801 from the centrifuge unit 200 to the storage rack 910 and / or vice versa. Alternatively or additionally, the handling system 400 may be arranged to move the cassette 801 from the centrifuge unit 200 to the loading station 700 and / or the opening device 600 and / or vice versa. Alternatively or additionally, the handling system 400 may be arranged to move the cassette 801 from the storage rack 910 to the first sample holder support 501 and / or vice versa.

[0163] The cell avidity analysis apparatus 100 may comprise one or multiple conditioning units 150, for example one in the form of a heater or a cooler for adapting and / or controlling the temperature in at least a part or section of the apparatus 100, preferably for at least adapting and / or controlling the temperature in a part 900 or section 900, which for instance may form an incubation station 900, in which the storage rack 910 is provided. Additionally or alternatively, one or more of the one or multiple conditioning units 150 may be for controlling the humidity and / or the air or gas pressure, for instance within at least a part or section of the apparatus, preferably at least a part or section provided with the at least one storage rack 910.

[0164] The apparatus 100, which at least in embodiments may be considered to form a so-called lab-in-a-box, may be in the form of a substantially self-contained apparatus. It may, at least in embodiments, for example allow users to conduct cell avidity analysis substantially without needing further tools or lab equipment.

[0165] The cell avidity analysis apparatus 100 may be arranged to conduct one or multiple steps of a cell avidity analysis substantially autonomously. For example, it may be arranged to conduct one or multiple one of the step A to Y described above in the summary of the invention.

[0166] The apparatus 100 may comprise a non-transitory computer-readable medium with instructions encoded thereon, and one or multiple processors configured to, when executing the instructions, perform such and / or operations. For example, the operations may be or comprise inverting the sample holder 802, in particular by means of the handling system 400, from a starting position, such as an upside up position, of the sample holder 802 into an inverted position, such as for example the upside down position of the sample holder 802, in particular while the sample holder 802 is housed inside the casing 803 of the cassette 801 . Further, the operations may be or comprise timing how long the sample holder 802, in particular the entire cassette 801 , is in its inverted position. Preferably, the one or multiple processors are further configured to, when executing the instructions, perform the operation of one or multiple, for instance all, of the steps A - Y described above in the summary of the invention.

[0167] In an embodiment, the cell avidity analysis apparatus 100 may comprise a non-transitory computer-readable medium with instructions encoded thereon, and one or multiple processors configured to, when executing the instructions, perform the operations of: inverting the sample holder 802, in particular by means of the handling system 400, from a starting position, such as an upside up position, of the sample holder 802 into an inverted position, such as for example the upside down position, of the sample holder 802, preferably while the sample holder 802 is inside the casing 803; placing the sample holder 802, preferably while it 802 is inside the casing 803, into the centrifuge unit 200 in its inverted position, in particular by means of the handling system 400; centrifuging said sample holder 802, preferably while it 802 is inside the casing 803; reinverting the sample holder 802, into its starting position, in particular by means of the handling system 400, wherein said reinverting for example is performable within the centrifuge unit 802 and / or after, or at least partially simultaneously with, an optional step of removing the sample holder 802 from the centrifuge unit 802; and measuring and / or controlling the duration of centrifuging of the sample holder 802.

[0168] Preferably, also the time interval between the moment the sample holder 802 is inverted from its initial starting position to its inverted position and the moment it 802 is reinverted to its original position, such as the upside up position, can be measured and / or controlled as well. Additionally or alternatively, also the time interval between the moment the sample holder 802 is inverted from its initial starting position to its inverted position and a later moment at which a further centrifuging starts after said sample holder 802 has been re-inverted to its original position, can be controlled and / or measured.

[0169] In preferred embodiments, the cell avidity analysis apparatus 100 performing said operations may also be arranged to perform additional operations. For example, it can be highly advantageous to capture an image of the effector cells being settled onto the target cells provided at the ceiling 8221 of the flow channel 851 of the sample holder 802. Preferably, said image, which can be made by means of the imaging device, can be made relatively shortly after the sample holder 802 has been centrifuged to assist the settling of the effector cells onto the ceiling of the inverted sample holder. In particular, the image may preferably be made while the sample holder 802 is still in its inverted, e.g. upside down, position, for example in order to counteract that effector cells which are not or only very weakly bound to the effector cells could come loose from the layer of target cells even before the sample holder is centrifuged in it is upright position. As such, a relatively good image of all settled down effector cells can be made. Preferably, the image of the settled down effector cells is made relatively shortly after centrifuging the sample holder in its inverted position, for example, within 100 seconds from the moment when the centrifuging stops, preferably within 60 seconds, more preferably witing 45 seconds, such for example about 30 seconds after centrifuging stopped.

[0170] By arranging the cell avidity analysis apparatus 100, in embodiments, such that it is configured for inverting, centrifuging and reinverting the sample holder 802, and for measuring and / or controlled the duration of centrifuging, and preferably for also measuring and / or controlling the time between inverting and reinverting and / or the time between inverting and centrifuging the reinverted sample holder, the spread in sedimentation time between the first effector cells settling down onto the target cells and the last effector cells settling down can be substantially reduced. Hence, the spread in incubation time between different ones of the effector cells can be substantially reduced. In this context, it is noted that it was observed that without such centrifuging, it may take a certain amount of time for effector cells to arrive at the target cell monolayer, before the effector cells and target cells can interact. This means that the actual contacting time of each effector cell that was in suspension and that arrived at and has had contact with the effector cells attached to the ceiling 8221 , may vary. This is because the distance and / or time spent by each target cell settling down from the suspension under the influence of gravity to the layer of target cells provided at the ceiling 8221 may vary, i.e. the arrival time for each effector cell in suspension to reach the target cells may vary.

[0171] The present inventors advantageously determined that by introducing, i.e. by exerting a, preferably relatively low, (centrifugal) force to the effector cells in suspension (referred to herein as an active settling force), the settling time can be significantly reduced as compared with settling times solely based on gravity, therewith advantageously improving accuracy of cellular avidity methods, such as outlined herein. An active settling force, as defined in these embodiments, refers to the force actively exerted on the effector cells in a direction towards the attached target cells, i.e. a force other than only the gravitational force. Such active settling force can allow for more accurate determination of cellular avidity parameters, in particular in scenarios wherein cells have or are suspected to have high k_on rates. In such scenarios, short defined contacting times (between effector cells and target cells) may be preferred and advantageously, using corrected defined contacting times, more in particular corrected defined contacting times obtained by exerting an active settling force with spin-assisted cell settling methods or the like, allows for more accurate cellular avidity determinations.

[0172] Hence, in embodiments, the apparatus 100 may thus be used for providing the effector cells in suspension in a flow channel 851 , 852, 853 with a ceiling surface 8221 provided with target cells attached thereto and a bottom surface, optionally the bottom surface coated with antifouling, and, subsequently exerting a settling force on the effector cells in the direction of the target cells attached to the ceiling surface. Preferably, in a further embodiment, after the effector cells are introduced in a flow channel in the upright position, the effector cells are first allowed to settle to the bottom of the flow channel, and subsequently, the holder with the flow channel is positioned in the upside down position and an active settling force is exerted to allow the effector cells to settle on the monolayer of target cells attached to the ceiling of the flow channel.

[0173] In preferred embodiments, the active settling force exerted can be a centrifugal force, in particular one exerted by means of the centrifuge unit. Preferably, the active settling force exerted is in the range of 2 g to 20 g (wherein g represents the standard gravity of 9.8 m / s2), more preferably about 2 g to 10 g, yet more preferably about 4 g to 6 g, such as for instance about 5 g.

[0174] For example since the active settling force may preferably be substantially lower than the force later applied to the effector cells to test their cellular biding strength when the sample holder is back in its initial upright position, in embodiments, the centrifuging unit may preferably be arranged to enable spinning at different speeds, for example at least two different rotational speeds including at least a relatively low rotational speed for applying the active settling force and a relatively high rotational speed for applying an avidity testing force to the effector cells.

[0175] The duration in which the active settling force is exerted is preferably in the range of 10 seconds to 1 minute, more preferably in the range of 30 seconds to 1 minute, yet more preferably in the range of 40 seconds to 50 seconds. Additionally, or alternatively, the maximum distance from a suspended effector cell to the monolayer of target cells is 1 mm or less, more preferably 0.5 mm or less. Hence, the height of the flow channel may preferably be 1 mm or less, more preferably 0.5 mm or less.

[0176] By configuring the apparatus 100 such that it can for example measure and / or control the duration of centrifuging during the spin-assisted cell settling, and preferably also the time between inverting and reinverting the sample holder 802 back to its upright position and / or the time between inverting the sample holder and centrifuging the reinverted sample holder, for example the spread in incubation time may not only be significantly reduced, but the (median) incubation time can also be established or monitored relatively accurately, which may be highly advantageously, at least in embodiments.

[0177] In a preferred method of using the apparatus, a sample holder 802 having a flow channel with a ceiling already provided with a monolayer of target cells is provided. Subsequently, when said sample holder 802 is in its upright position, a liquid suspension comprising suspended effector cells is fed into the flow channel.

[0178] Subsequently, the initially suspended effector cells may then be allowed to settle on the bottom of the flow channel. For example, this may occur when the sample holder is held in the incubation station 900, in which, additionally or alternatively, the sample holder and / or its contents can be brought to and / or kept at a desired temperature, e.g. a temperature of about 37° C.

[0179] Subsequently, preferably when substantially all effector cells, such as for example at least 90% or at least 95% or even at least 98% thereof, are settled on the bottom of the flow channel, the sample holder can be inverted I flipped and can thereafter be spun I centrifuged in order to let the effector cells settle onto the ceiling provided with the target cells. As mentioned above, subsequently, an image may be captured of at least a part of the effector cells settled down onto the target cells at the ceiling of the flow channel of the inverted sample holder, in particular before the sample holder is re-inverted into its upright position in which it subsequently can be centrifuged I spun in order to apply a force to the effector cells to test their cellular biding strength.

[0180] It will be appreciated that, additionally, other steps and operations may be performed, such as for example the operation of making a further, e.g. second, image of the layer of target cells to which the effector cells were bound, wherein said further image is made after centrifuging the sample holder in its upright position, in particular in order to enable comparing the earlier image and the further image, especially such as to determine how many effector cells came loose from the layer of target cells. It will thus be appreciated by the skilled person that such operations and / or steps, in particular ones described in this description and / or the appending claims, can also be incorporated in methods of using the cell avidity analysis apparatus 100. Further, it is evident to the skilled person that, in embodiments, the apparatus 100 may thus be arranged for performing such method steps and / or operations, also when not explicitly stated so herein.

[0181] The invention is not restricted to the embodiments described herein. It will be understood that many variants are possible.

[0182] For example, it will be appreciated that the apparatus may be arranged to communicate with a computer, for example in order to provide output, in particular with regard to the cell avidity analysis, and / or in order to receive input, for example with regard to a cell avidity analysis to be performed. It also possible that the device, additionally or alternatively, comprises one or more output or display devices and / or one or more input devices or the like.

[0183] Such and other variants will be obvious for the person skilled in the art and are considered to lie within the scope of the invention as formulated in the following claims.

Claims

36CLAIMS1. Cell avidity analysis apparatus (100), comprising: a housing (110) for housing components of the apparatus (100); a centrifuge unit (200) located inside the housing (110), said centrifuge unit (200) being arranged for holding and centrifuging a sample holder (802), preferably a sample holder (802) held within a substantially hermetically sealed casing (803); and an imaging device (300), preferably a microscopy device, for imaging at least a first section of the sample holder (802), preferably said first section being formed by a section of a flow channel (851 , 852, 853) of said sample holder (802), wherein said imaging device (300) being located inside the housing (110), wherein said imaging device (300) is located outside the centrifuge unit (200), and wherein the apparatus (100) further comprises a handling system (400), the handling system (400) being located inside the housing (110), and the handling system (400) being arranged for placing the sample holder (802) inside the centrifuge (200) and / or arranged for taking the sample holder (802) out of the centrifuge (200) and towards the imaging device (300).

2. Cell avidity analysis apparatus (100) according to claim 1 , wherein the apparatus (100) comprises a first sample holder support (501), the first sample holder support (501) being located inside the housing (110), and the first sample holder support (501) being for supporting the sample holder (802) when the imaging device is imaging at least the first section of the sample holder (802), wherein the handling system (400) is arranged for removing the sample holder (802), in particular when held in the casing (803), from the centrifuge unit (200) and placing the sample holder (802) at, on and / or in the first sample holder support (501).

3. Cell avidity analysis apparatus (100) according to claim 2, wherein the first sample holder support (501) being provided with a first stop surface or abutment against which the sample holder (802) can rest, said sample37 holder further being provided with an opposing element arranged for applying pressure or force against the sample holder such as to press in against said first stop surface; and / or wherein the first sample holder support (501) and the imaging device (300) are movable with respect to each other in order to enable bringing a respective one of multiple sections of the sample holder (802), preferably multiple sections of multiple ones of multiple flow channels (851 , 852, 853) of the sample holder (802), into a field of view of the imaging device (300); and / or wherein the handling system (400) is arranged for turning the sample holder (802) upside down, preferably when said sample holder (802) is not located inside the casing (803), if any.

4. Cell avidity analysis apparatus (100) according to any one of the preceding claims wherein the apparatus (100), preferably its handling system (400), is arranged for removing the sample holder (802) from the casing (803).

5. Cell avidity analysis apparatus (100) according to any one of the preceding claims, wherein the sample holder (802) comprises at least one flow channel (851), and preferably multiple flow channels (851 , 852, 853), each extending between a respective channel inlet (851A, 852A, 853A) and a respective channel outlet (851 B, 852B, 853B), wherein the apparatus (100) further comprises a loading station (700), located inside the housing (110), wherein the loading station (700) is provided with a second sample holder support for holding the sample holder (802), which for instance may be present in an opened casing (803) or part (831) of said casing (803), more preferably a casing of which a second casing part (832), which may form a lid of the casing, has been temporarily removed, and wherein the loading station (700) is further provided with at least one liquid handling module (710), such as for example a pipetting robot, said at least one liquid handling module (710) being located inside the housing (110), said liquid handlingmodule (710) being arranged for loading a liquid into at least one of the one or multiple flow channels (851 , 852, 853) of the sample holder (802), for instance a sample holder in the form of a 96-well, 384-well or 1536-well microplate conforming to the ANSI SLAS standards, preferably wherein the liquid handling module comprise at least one set including a liquid dispenser for liquid insertion into the flow channel and a liquid remover for liquid removal from said flow channel, in particular wherein the liquid handling module (710) is arranged such that said liquid dispenser can dispense into the channel inlet (851A, 852A, 853A) while said liquid remover simultaneously aspirates from the channel outlet (851 B, 852B, 853B) of the same flow channel (851 , 852, 853), for example in particular to facilitate achieving a relatively constant flow and / or facilitate counteracting overflow or emptying of said flow channel, and / or preferably wherein the loading station (700) is arranged to load liquid into multiple ones of multiple flow channels (851 , 852, 853) of the sample holder (802) at least partly simultaneously, more preferably wherein the multiple ones comprise at least four flow channels, more preferably at least eight flow channels.

6. Cell avidity analysis apparatus (100) according to any one of the preceding claims, wherein the centrifuge unit (200) comprises a rotor (210) provided with multiple receptacles (220, 230), each one of which is arranged for receiving and holding a sample holder (802), preferably a sample holder held within a cassette’s casing (803) said receptacles (220, 230) being arranged equidistantly and / or rotationally symmetrically about the rotational axis (211) of the rotor (210), preferably wherein each receptacle (220, 230)is hingedly mounted with respect to the rotor (210) in order to enable to hinge or swing about a hinging axis (A220, A230), said hinging axis extending transverse to the rotational axis (211) of the rotor (210) and more preferably also extending substantially tangential to a virtual circle surrounding said rotor (210).

7. Cell avidity analysis apparatus (100) according to claim 6,wherein each of the receptacles (220, 230) comprises a tray (221 , 231) for receiving and holding the respective sample holder (802), which preferably may be part of a cell avidity analysis cassette (801), and the centrifuge unit (200) is arranged such that, in a rest position of the centrifuge (200), said tray (220, 230) extends in a substantially flat or horizontal position; and / or wherein at least one of the receptacles (220, 230) holds a releasably received counterweight, preferably one substantially dimensioned and / or substantially shaped as the casing (803) of the sample holder (802).

8. Cell avidity analysis apparatus (100) according to any one of the preceding claims, wherein said apparatus (100) further comprises an opening device (600) arranged for opening a casing (803) which houses the sample holder (802), said opening device being located inside the housing (110) of the apparatus (100), wherein the opening device is arranged for receiving and engaging a first casing part (831) of the casing (803), wherein the apparatus (100), for instance its handling system (400), is arranged for engaging a second casing part (832) of the casing (803) and removing the second casing part (832) from the first casing part (831), preferably wherein the opening device (600) is further provided with an opening mechanism (610) for unlocking one or multiple locks (804) or locking mechanisms (804), if any, for releasably locking the first casing part (831) with respect to the second casing part (832).

9. Cell avidity analysis apparatus (100) according to claim 8, wherein the opening mechanism (610) comprises at least one, and preferably at least three, such as for instance four, push elements (611 , 612, 613, 614), preferably push rods, for unlocking or disengaging a respective lock (804) formed as a releasable snap lock (840).

10. Cell avidity analysis apparatus (100) according to any one of the preceding claims,wherein the apparatus (100) further comprises one or more storage racks (910) for storing a sample holder, preferably for storing a cassette (801) comprising a casing (803) housing the sample holder (802) therewithin, said one or more storage racks (910) being located inside the housing (110) of the apparatus (100), and wherein the handling system is arranged to move the sample holder (802), preferably the cassette provided with said sample holder, from the storage rack (910) to the loading station and / or the opening device (600), if any, which opening device (600) may be part of the loading station (700), and / or wherein the handling system (400) is arranged to move the sample holder, preferably the cassette (901) provided with said sample holder, from the loading station (700) and / or the opening device (600), if any, which opening device may be part of the loading station, to the storage rack (910).

11. Cell avidity analysis apparatus (100) according to any one of the preceding claims, wherein the handling system (400) is arranged to move the sample holder, preferably the cassette provided with said sample holder, from the loading station and / or the opening device to the first sample holder support and / or vice versa, and / or wherein the handling system (400) is arranged to move the sample holder, preferably the cassette provided with said sample holder, from the centrifuge unit (200) to the first sample holder support (501) and / or vice versa, and / or wherein the handling system (400) is arranged to move the sample holder, preferably the cassette (801) provided with said sample holder, from the centrifuge unit (200) to the storage rack (910) and / or vice versa, and / or wherein the handling system (400) is arranged to move the sample holder, preferably the cassette provided with said sample holder, from the centrifuge unit (200) to the loading station (700) and / or the opening device (600) and / or vice versa, and / or wherein the handling system (400) is arranged to move the sample holder, preferably the cassette provided with said sample holder (802), from the storage rack (910) to the first sample holder support (501) and / or vice versa.

12. Cell avidity analysis apparatus (100) according to any one of the preceding claims, further comprising at least one of a heater or a cooler for adapting and / or41 controlling the temperature in at least a part or section (900) of the apparatus (100), preferably for at least adapting and / or controlling the temperature in a part or section in which the storage rack (910) is provided.

13. Cell avidity analysis apparatus (100) according to any one of the preceding claims, wherein the apparatus comprises a non-transitory computer-readable medium with instructions encoded thereon, and one or multiple processors configured to, when executing the instructions, perform the operations of: inverting the sample holder, in particular by means of the handling system (400), from a starting position, such as an upside up position, of the sample holder (802) into an inverted position, such as for example the upside down position of the sample holder, preferably while the sample holder (802) is inside the casing (803); and timing how long the sample holder is in its inverted position.

14. Cell avidity analysis apparatus (100) according to claim 13, wherein the one or multiple processors are further configured to, when executing the instructions, perform the operation of: once a predetermined period of time has lapsed while the sample holder (802) is in its inverted position, preferably while inside the casing (803), re-inverting the sample holder (802), preferably the entire cassette (801), in particular by means of the handling system (400), from said inverted position of the sample holder (802) back to the starting position of the sample holder (802), preferably wherein the one or multiple processors are further configured to, when executing the instructions, perform the operation of placing the sample holder (802), preferably the entire cassette (801), in the centrifuge unit (200) and centrifuging said sample holder (802).

15. Cell avidity analysis apparatus (100) according to any one claims 1-12, wherein the apparatus (100) comprises a non-transitory computer-readable medium with instructions encoded thereon, and one or multiple processors configured to, when executing the instructions, perform the operations of:42 inverting the sample holder (802), in particular by means of the handling system (400), from a starting position, such as an upside up position, of the sample holder (802) into an inverted position, such as for example the upside down position, of the sample holder (802), preferably while the sample holder (802) is inside the casing (803); placing the sample holder (802), preferably while it (802) is inside the casing (803), into the centrifuge unit (200) in its inverted position, in particular by means of the handling system (400); centrifuging said sample holder (802), preferably while it (802) is inside the casing (803); reinverting the sample holder (802) into its starting position, in particular by means of the handling system (400), wherein said reinverting for example is performable within the centrifuge unit (802) and / or after, or at least partially simultaneously with, an optional step of removing the sample holder (802) from the centrifuge unit (802); and controlling and / or measuring the duration of centrifuging of the sample holder (802), and preferably also controlling and / or measuring at least one of: the time interval between the moment the sample holder (802) is inverted from its initial starting position to its inverted position and the moment it (802) is reinverted to its original position, such as the upside up position; and the time interval between the moment the sample holder (802) is inverted from its initial starting position to its inverted position and a later moment at which a further centrifuging starts after said sample holder (802) has been re-inverted to its original position, such as the upside up position, preferably wherein the one or multiple processors are further configured to, when executing the instructions, perform the operations of: placing the sample holder (802), preferably the entire cassette (801), unit (200) in its original position in the centrifuge; and further centrifuging said sample holder (802) after said sample holder (802) has been re-inverted to its original position.

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