Anti-CLEC12a antibodies and medical uses thereof

Abstract

The present invention relates to anti-CLEC12A antibodies and the antigen-binding fragments thereof. The present invention further relates to pharmaceutical compositions and diagnostic tests comprising the anti-CLEC12A antibodies or antigen binding fragments thereof, and the uses of such antibodies for the treatment and diagnosis of microbial infections.

Description

[0001] ANTI-CLEC12A ANTIBODIES AND MEDICAL USES THEREOF

[0002] Technical Field of the Invention

[0003] The present invention relates to anti-CLEC12A antibodies and the antigen- binding fragments thereof. The present invention further relates to pharmaceutical compositions and diagnostic tests comprising the anti-CLEC12A antibodies or antigen binding fragments thereof, and the uses of such antibodies for the treatment of microbial infections, and in particular, fungal infections.

[0004] Background to the Invention

[0005] Myeloid Inhibitory C-type Lectin (CLEC12A, or MICL) antigen is an inhibitory C-type lectin receptor expressed predominantly by myeloid cells. Inhibitory receptors regulate immune cell activation, and loss or mutation of inhibitory receptors is often associated with excessive inflammation and host tissue damage.

[0006] The inventors of the present invention discovered a key mechanism by which

[0007] CLEC12A regulates neutrophil activation and nuclear extracellular trap (NET) formation. Neutrophils are one of the main cell types involved in the inflammatory response and are among the first line defence against a large number of pathogens.

[0008] Neutrophils are activated based on pro-inflammatory signals that trigger a variety of antibody effector functions depending on their surface receptor composition and intracellular protein content. For example, neutrophils can respond to microbes via phagocytosis, generation of reactive oxygen species (ROS), degranulation or release of neutrophil extracellular traps (NETs). NETs are extracellular structures composed of

[0009] DNA and cytosolic, granular and nuclear proteins assembled on a scaffold of decondensed chromatin. NETs protect against infection by containing, neutralising and killing microorganisms, such as fungi, bacteria and viruses.

[0010] Anti-CLEC12A antibodies that bind CLEC12A affect the activity of CLEC12A and its associated mechanism. Due to its role in inflammation and immune response, there is a need to develop antibodies that bind CLEC12A.

[0011] It is an aim of embodiments of the present invention to provide an anti- CLEC12A antibody that binds CLEC12A and affects the activity of CLEC12A and its associated mechanism. It is a further aim of the present invention to provide an anti- CLEC12A antibody for the treatment of microbial infections, in particular, fungal infections.

[0012] It is also an aim of embodiments to the invention to overcome or mitigate at least one problem of the prior art, whether disclosed herein or not.

[0013] Summary of the Invention

[0014] According to a first aspect of the present invention, there is provided an anti- CLEC12A antibody or antigen-binding fragment thereof for use in the treatment or diagnosis of a microbial infection.

[0015] The antibody or antigen-binding fragment thereof according to the first aspect of the invention may be as described and defined for the second or third aspects of the invention hereinbelow, including any embodiments thereof.

[0016] The term “antibody or antigen-binding fragment thereof’ encompasses (a) an antibody, (b) an antigen-binding fragment of an antibody, or (c) a derivative of an antibody. An “antibody” refers to an immunoglobulin molecule that is typically composed of two identical pairs of polypeptide chains, each pair having one heavy chain (HC) and one light chain (LC). The term “antigen-binding fragment” refers to immunologically active portions of immunoglobulin molecules (i.e. molecules that contain an antigen binding site that specifically binds an antigen). Each heavy chain comprises a heavy chain variable region (HCVR or VH) and a heavy chain constant region. Each light chain comprises a light chain variable region (LCVR or VL) and a light chain constant region. The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g. effector cells). The HCVR and the LCVR regions can be further subdivided into regions of hyperavailability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). Each HCVR and LCVR comprise three CDRs and four FRs arranged from the N- terminus to the C-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of each HCVR and LCVR form the antibody binding site.

[0017] In some embodiments, the anti-CLEC12A antibody or antigen-binding fragment thereof is used in the treatment of microbial infections whose control is increased through regulation of NET formation and / or regulation of inflammation.

[0018] In some embodiments, the anti-CLEC12A antibody or antigen-binding fragment thereof is used in the treatment or diagnosis of a fungal, bacterial or viral infection. In some embodiments, the anti-CLEC12A antibody or antigen-binding fragment thereof is used in the treatment of an infection with a Candida species, for example, Candida Albicans.

[0019] In some embodiments, the anti-CLEC12A antibody or antigen-binding fragment thereof is used in the treatment of an infection with Aspergillus fumigatus.

[0020] In some embodiments, the anti-CLEC12A antibody or antigen-binding fragment thereof is used in the treatment or diagnosis of an infection with Rhizopus delemar.

[0021] In some embodiments, the anti-CLEC12A antibody or antigen-binding fragment thereof is used in the treatment or diagnosis of vulvovaginal candidiasis (VVC) infection.

[0022] In some embodiments, the anti-CLEC12A antibody or antigen-binding fragment thereof is used in the treatment or diagnosis of mucormycosis infection.

[0023] According to another aspect of the invention there is provided an anti- CLEC12A antibody or antigen-binding fragment thereof for use in the regulation of NET formation to control inflammation.

[0024] The NET formation may be protective (e.g., NET formation may cause inflammation which prevents, ameliorates or reduces microbial infection).

[0025] According to a second aspect of the present invention, there is provided an anti- CLEC12A antibody or antigen-binding fragment thereof, comprising one of the following: (i) a heavy chain variable region comprising a CDR1 encoded by a nucleic acid sequence of SEQ ID NO: 1, a CDR2 encoded by a nucleic acid sequence of SEQ ID NO:2, and a CDR3 encoded by a nucleic acid sequence of SEQ ID NO: 3; and a light chain variable region comprising a CDR1 encoded by a nucleic acid sequence of SEQ ID NO: 4, a CDR2 encoded by a nucleic acid sequence of SEQ ID NO: 5, and a CDR3 encoded by a nucleic acid sequence of SEQ ID NO: 6;

[0026] (ii) a heavy chain variable region comprising a CDR1 encoded by a nucleic acid sequence of SEQ ID NO: 7, a CDR2 encoded by a nucleic acid sequence of SEQ ID NO: 8, and a CDR3 encoded by a nucleic acid sequence of SEQ ID NO: 9; and a light chain variable region comprising a CDR1 encoded by a nucleic acid sequence of SEQ ID NO: 10, a CDR2 encoded by a nucleic acid sequence of SEQ ID NO: 11, and a CDR3 encoded by a nucleic acid sequence of SEQ ID NO: 12;

[0027] (iii) a heavy chain variable region comprising a CDR1 encoded by a nucleic acid sequence of SEQ ID NO: 13, a CDR2 encoded by a nucleic acid sequence of SEQ ID NO: 14, and a CDR3 encoded by a nucleic acid sequence of SEQ ID NO: 15; and a light chain variable region comprising a CDR1 encoded by a nucleic acid sequence of SEQ ID NO: 16, a CDR2 encoded by a nucleic acid sequence of SEQ ID NO: 17, and a CDR3 encoded by a nucleic acid sequence of SEQ ID NO: 18.

[0028] The antibody or antigen-binding fragment thereof according to the second aspect of the invention may be as described and defined for the third aspect of the invention hereinbelow, including any embodiments thereof.

[0029] In some embodiments, the anti-CLEC12A antibody or antigen-binding fragment thereof, comprises a heavy chain variable region comprising a CDR1 encoded by a nucleic acid sequence of SEQ ID NO: 1, a CDR2 encoded by a nucleic acid sequence of SEQ ID NO: 2, and a CDR3 encoded by a nucleic acid sequence of SEQ ID NO: 3; and a light chain variable region comprising a CDR1 encoded by a nucleic acid sequence of SEQ ID NO: 4, a CDR2 encoded by a nucleic acid sequence of SEQ ID NO: 5, and a CDR3 encoded by a nucleic acid sequence of SEQ ID NO: 6.

[0030] In some embodiments, the anti-CLEC12A antibody or antigen-binding fragment thereof, comprises a heavy chain variable region comprising a CDR1 encoded by a nucleic acid sequence of SEQ ID NO: 7, a CDR2 encoded by a nucleic acid sequence of SEQ ID NO: 8, and a CDR3 encoded by a nucleic acid sequence of SEQ ID NO: 9; and a light chain variable region comprising a CDR1 encoded by a nucleic acid sequence of SEQ ID NO: 10, a CDR2 encoded by a nucleic acid sequence of SEQ ID NO: 11, and a CDR3 encoded by a nucleic acid sequence of SEQ ID NO: 12.

[0031] In some embodiments, the anti-CLEC12A antibody or antigen-binding fragment thereof, comprises a heavy chain variable region comprising a CDR1 encoded by a nucleic acid sequence of SEQ ID NO: 13, a CDR2 encoded by a nucleic acid sequence of SEQ ID NO: 14, and a CDR3 encoded by a nucleic acid sequence of SEQ ID NO: 15; and a light chain variable region comprising a CDR1 encoded by a nucleic acid sequence of SEQ ID NO: 16, a CDR2 encoded by a nucleic acid sequence of SEQ ID NO: 17, and a CDR3 encoded by a nucleic acid sequence of SEQ ID NO: 18.

[0032] In some embodiments, the nucleic acid sequence comprises a nucleic acid substitution which does not alter the amino acid encoded (i.e. a silent mutation). The nucleic acid substitution may not alter the CDR encoded.

[0033] According to a third aspect of the present invention, there is provided an anti- CLEC12A antibody or antigen-binding fragment thereof, comprising one of the following:

[0034] (i) a heavy chain variable region comprising an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 25 and a light chain variable region comprising an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 26;

[0035] (ii) a heavy chain variable region comprising an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 27 and a light chain variable region comprising an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 28;

[0036] (iii) a heavy chain variable region comprising an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 29 and a light chain variable region comprising an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 30.

[0037] The anti-CLEC12A antibody or antigen-binding fragment thereof, may comprise one of the following: (i) a heavy chain variable region comprising an amino acid sequence with at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 25 and a light chain variable region comprising an amino acid sequence with at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 26;

[0038] (ii) a heavy chain variable region comprising an amino acid sequence with at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 27 and a light chain variable region comprising an amino acid sequence with at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 28;

[0039] (iii) a heavy chain variable region comprising an amino acid sequence with at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 29 and a light chain variable region comprising an amino acid sequence with at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 30.

[0040] The anti-CLEC12A antibody or antigen-binding fragment thereof, may comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID

[0041] NO: 25 and a light chain variable region comprising the amino acid sequence of SEQ

[0042] ID NO: 26. The anti-CLEC12A antibody or antigen-binding fragment thereof, may comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 28.

[0043] The anti-CLEC12A antibody or antigen-binding fragment thereof, may comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 29 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 30.

[0044] The amino acid sequences of the heavy chain variable region and / or the light chain variable region described above may comprise one or more conservative amino acid substitutions. The conservative amino acid substitution(s) may not alter the sequence of a CDR. The amino acid sequences described above may comprise no more than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid substitutions.

[0045] In some embodiments, the anti-CLEC12A antibody or antigen-binding fragment thereof of any of the first, second or third aspect of the invention binds to CLEC12A, and affects at least one activity associated with CLEC12A. The CLEC12A may comprise the sequence defined in t ncbi.nlm.nih.gov / nuccore / NM 138337.6 or may be an isoform thereof.

[0046] The activities associated with CLEC12A may comprise at least one activity selected from the group consisting of: the regulation of nuclear extracellular trap (NET) formation, respiratory burst enhancement, enhancement of formation of extracellular traps, enhancement of inflammatory mediator production (eg: cytokines and chemokine) and any combinations thereof. In some embodiments, the anti-CLEC12A antibody or antigen-binding fragment thereof of any of the first, second or third aspect of the present invention is a human, chimeric, humanised or dehumanised antibody or an antigen-binding fragment thereof. The anti-CLEC12A antibody or antigen-binding fragment thereof may be in multimeric form, such as a dimer, trimer, or a higher-order multimer of monomeric antibodies. The anti-CLEC12A antibody or antigen-binding fragment thereof may be a monoclonal antibody or fragment thereof. The anti-CLEC12A antibody or antigenbinding fragment thereof may be a recombinant antibody, a bispecific antibody, a polyclonal antibody, or an antigen-binding fragments thereof.

[0047] In some embodiments, the anti-CLEC12A antibody or antigen binding fragment thereof of either of the second or third aspect of the present invention is used in the treatment of a microbial infection.

[0048] In some embodiments, the anti-CLEC12A antibody or antigen binding fragment thereof of either of the second or third aspect of the present invention is used in the diagnosis of a microbial infection.

[0049] The anti-CLEC12A antibody or antigen-binding fragment thereof of either of the second or third aspect of the present invention may be used in the treatment or diagnosis of a microbial infection whose control is increased through regulation of NET formation.

[0050] The anti-CLEC12A antibody or antigen-binding fragment thereof of either of the second or third aspect of the present invention may be used in the treatment or diagnosis of a fungal, bacterial or viral infection. The anti-CLEC12A antibody or antigen-binding fragment thereof of either of the second or third aspect of the present invention may be used in the treatment of an infection with Aspergillus fumigatus .

[0051] The anti-CLEC12A antibody or antigen-binding fragment thereof of either of the second or third aspect of the present invention may be used in the treatment or diagnosis of an infection with a Candida species, for example, Candida Albicans.

[0052] In some embodiments, the anti-CLEC12A antibody or antigen-binding fragment thereof of either the second or third aspect of the present invention is used in the treatment or diagnosis of an infection with Rhizopus delemar.

[0053] In some embodiments, the anti-CLEC12A antibody or antigen-binding fragment thereof of either the second or third aspect of the present invention is used in the treatment or diagnosis of a vulvovaginal candidiasis infection.

[0054] In some embodiments, the anti-CLEC12A antibody or antigen-binding fragment thereof of either the second or third aspect of the present invention is used in the treatment or diagnosis of a mucormycosis infection.

[0055] According to a fourth aspect of the present invention, there is provided a nucleic acid sequence encoding the anti-CLEC12A antibody or antigen-binding fragment thereof of any of the first, second or third aspects of the present invention.

[0056] In some embodiments, the nucleic acid sequence comprises a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 19 which encodes the heavy chain variable region of the anti-CLEC12A antibody or antigen-binding fragment thereof, and a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 20 which encodes the light chain variable region of the anti-CLEC12A antibody or antigen-binding fragment thereof. Preferably, the nucleic acid sequence comprises a nucleic acid sequence of SEQ ID NO: 19 which encodes the heavy chain variable region of the anti-CLEC12A antibody or antigen-binding fragment thereof, and a nucleic acid sequence of SEQ ID NO: 20 which encodes the light chain variable region of the anti-CLEC12A antibody or antigen-binding fragment thereof.

[0057] In some embodiments, the nucleic acid sequence comprises a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 21 which encodes the heavy chain variable region of the anti-CLEC12A antibody or antigen-binding fragment thereof, and a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 22 which encodes the light chain variable region of the anti-CLEC12A antibody or antigen-binding fragment thereof. Preferably, the nucleic acid sequence comprises a nucleic acid sequence of SEQ ID NO: 21 which encodes the heavy chain variable region of the anti-CLEC12A antibody or antigen-binding fragment thereof, and a nucleic acid sequence of SEQ ID NO: 22 which encodes the light chain variable region of the anti-CLEC12A antibody or antigen-binding fragment thereof.

[0058] In some embodiments, the nucleic acid sequence comprises a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 23 which encodes the heavy chain variable region of the anti-CLEC12A antibody or antigen-binding fragment thereof, and a nucleic acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 24 which encodes the light chain variable region of the anti-CLEC12A antibody or antigen-binding fragment thereof. Preferably, the nucleic acid sequence comprises a nucleic acid sequence of SEQ ID NO: 23 which encodes the heavy chain variable region of the anti-CLEC12A antibody or antigen-binding fragment thereof, and a nucleic acid sequence of SEQ ID NO: 24 which encodes the light chain variable region of the anti-CLEC12A antibody or antigen-binding fragment thereof.

[0059] In some embodiments, the nucleic acid sequence comprises a nucleic acid substitution which does not alter the amino acid encoded (i.e. a silent mutation). The nucleic acid substitution may not alter the CDR encoded.

[0060] According to a fifth aspect of the present invention, there is provided a vector comprising the nucleic acid sequence of the fourth aspect of the present invention.

[0061] The nucleic acid sequence may be as described hereinabove for the fourth aspect of the invention and may include an optional or combination of optional features described for the fourth aspect of the invention.

[0062] The vector may be a recombinant vector.

[0063] The vector may be viral or non-viral vector.

[0064] The vector may be an expression vector, a plasmid, a phage, or a viral vector.

[0065] According to a sixth aspect of the invention, there is provided a host cell comprising a vector of the fifth aspect of the present invention. The vector may be as described hereinabove for the fifth aspect of the invention and may include any optional or combination of optional features described for the fifth aspect of the invention.

[0066] The host cell may be a prokaryotic or eukaryotic cell. The host cell may be derived from a mammal.

[0067] According to a sixth aspect of the present invention, there is provided a pharmaceutical composition comprising the anti-CLEC12A antibody or antigenbinding fragment thereof of any of the first, second or third aspects of the present invention or a vector according to the fifth aspect of the present invention, and one or more pharmaceutically acceptable diluents or excipients.

[0068] The anti-CLEC12A antibody or antigen-binding fragment thereof may be as described hereinabove for the first, second or third aspects of the present invention and may include any optional or combination of optional features described for the first, second or third aspects of the invention.

[0069] Pharmaceutically acceptable diluents or excipients include water, saline, dextrose, glycerol, ethanol, salts, pH buffers, phosphate buffered saline, emulsifiers, or wetting agents.

[0070] The pharmaceutical composition may comprise one or more additional therapeutic agents. Therapeutic agents may include small molecules, antifungal agents, antibiotics and other antimicrobial agents, for example.

[0071] According to a seventh aspect of the present invention, there is provided a method of treating an individual with a microbial infection, the method comprising administering to an individual a therapeutically effective amount of the anti-CLEC12A antibody or antigen-binding fragment thereof of any of the first, second or third aspects of the invention.

[0072] The anti-CLEC12A antibody or antigen-binding fragment thereof may be as described hereinabove for the first, second or third aspects of the present invention and may include any optional or combination of optional features described for the first, second or third aspects of the invention.

[0073] In some embodiments, the anti-CLEC12A antibody or antigen-binding fragment thereof is administered in the form of the pharmaceutical composition of the sixth aspect of the invention.

[0074] The pharmaceutical composition may be as described for the sixth aspect of the invention and may include any optional or combination of optional features described for the sixth aspect of the invention.

[0075] The individual may be a mammal, preferably a human.

[0076] The method may relate to the treatment of an individual with a microbial infection.

[0077] The method may relate to the treatment of an individual with a microbial infection whose control can be increased through regulation of NET formation.

[0078] The method may relate to the treatment of an individual with a fungal, bacterial or viral infection.

[0079] The method may relate to the treatment of an individual with an Aspergillus fumigatus infection. The method may relate to treating an individual suffering from an infection with a Candida species, for example, Candida Albicans.

[0080] The method may relate to treating an individual suffering from an infection with Rhizopus delemar.

[0081] The method may relate to the treatment of an individual suffering with vulvovaginal candidiasis infection.

[0082] The method may relate to the treatment of an individual suffering with mucormycosis infection.

[0083] A “therapeutically effective amount” refers to an amount that is effective for an intended therapeutic purpose.

[0084] The therapeutically effective amount of an antibody typically ranges from about 0.001 to 500 mg / kg of the body weight of the individual, preferably about 0.05 to 100 mg / kg of the body weight of the individual. However, the dosage level to be administered will depend on a number of factors such as the type and severity of the disease, condition or infection to be treated / prevented, the route of administration, the time of administration, the duration of treatment, the frequency of treatment, as well as the age, weight, sex, condition, general health of the individual being treated.

[0085] The anti-CLEC12A antibody or antigen-binding fragment thereof may be administered only once or on multiple occasions. Intervals between doses can be, for example, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 7 days, 2 weeks, 1 month, 3 months, 6 months, or yearly. Administration may occur multiple times per day, multiple times per week, once per week, once every two weeks, once every three weeks, once every four weeks, once every 3 months, once every 6 months, or multiple times a year.

[0086] The anti-CLEC12A antibody or antigen-binding fragment thereof may be administered by enteral, parenteral, topical or inhalation administration. In preferred embodiments, the anti-CLEC12A antibody or antigen-binding fragment thereof may be administered parenterally. The anti-CLEC12A antibody or antigen-binging fragment thereof may be administered intravenously by injection or infusion over time. The anti- CLEC12A may be administered by intravascular, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intratumoral, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection or infusion.

[0087] The anti-CLEC12A antibody or antigen-binding fragment thereof may be administered in combination with one or more additional therapeutic agent, drug, or treatment. The anti-CLEC12A antibody or antigen-binding fragment thereof may be a combination therapy.

[0088] According to an eighth aspect of the present invention, there is provided an anti- CLEC12A antibody or antigen-binding fragment thereof comprising one of the following:

[0089] (i) a heavy chain variable region comprising at least one CDR encoded by a nucleic acid sequence selected from SEQ ID NO: 1, 2 and 3, and a light chain variable region comprising at least one CDR encoded by a nucleic acid sequence selected from SEQ ID NO: 4, 5 and 6; (ii) a heavy chain variable region comprising at least one CDR encoded by a nucleic acid sequence selected from SEQ ID NO: 7, 8 and 9, and a light chain variable region comprising at least one CDR encoded by a nucleic acid sequence selected from SEQ ID NO: 10, 11 and 12;

[0090] (iii) a heavy chain variable region comprising at least one CDR encoded by a nucleic acid sequence selected from SEQ ID NO: 13, 14 and 15, and a light chain variable region comprising at least one CDR encoded by a nucleic acid sequence selected from SEQ ID NO: 16, 17 and 18.

[0091] In some embodiments, the anti-CLEC12A antibody or antigen-binding fragment thereof comprises one of the following:

[0092] (i) a heavy chain variable region comprising one CDR encoded by at nucleic acid sequence selected from SEQ ID NO: 1, 2 and 3, and a light chain variable region comprising one CDR encoded by a nucleic acid sequence selected from SEQ ID NO: 4, 5 and 6;

[0093] (ii) a heavy chain variable region comprising one CDR encoded by a nucleic acid sequence selected from SEQ ID NO: 7, 8 and 9, and a light chain variable region comprising one CDR encoded by a nucleic acid sequence selected from SEQ ID NO: 10, 11 and 12;

[0094] (iii) a heavy chain variable region comprising one CDR encoded by a nucleic acid sequence selected from SEQ ID NO: 13, 14 and 15, and a light chain variable region comprising one CDR encoded by a nucleic acid sequence selected from SEQ ID NO: 16, 17 and 18. In some embodiments, the anti-CLEC12A antibody or antigen-binding fragment thereof comprises one of the following:

[0095] (i) a heavy chain variable region comprising two CDRs encoded by at nucleic acid sequence selected from SEQ ID NO: 1, 2 and 3, and a light chain variable region comprising two CDRs encoded by a nucleic acid sequence selected from SEQ ID NO: 4, 5 and 6;

[0096] (ii) a heavy chain variable region comprising two CDRs encoded by a nucleic acid sequence selected from SEQ ID NO: 7, 8 and 9, and a light chain variable region comprising two CDRs encoded by a nucleic acid sequence selected from SEQ ID NO: 10, 11 and 12;

[0097] (iii) a heavy chain variable region comprising two CDRs encoded by a nucleic acid sequence selected from SEQ ID NO: 13, 14 and 15, and a light chain variable region comprising two CDRs encoded by a nucleic acid sequence selected from SEQ ID NO: 16, 17 and 18.

[0098] The anti-CLEC12A antibody or antigen-binding fragment thereof of the eighth aspect of the invention may be for use as described and defined hereinabove for the first, second or third aspects of the invention.

[0099] Detailed Description of the Invention

[0100] In order that the invention may be more clearly understood embodiments thereof will now be described, by way of example only, with reference to the accompanying drawings, of which: Figure 1 shows the fluorescence of A. fumigatus hyphae- induced NETs bound to

[0101] Sytox green in (a) isolated neutrophils from WT and CLEC12A- deficient (KO) mice, or (b) human neutrophils in the presence of anti¬

[0102] CLEC12A antibodies according to embodiments of the first, second and third aspect of the present invention and isotype control antibodies

[0103] (isotype). The fluorescence background signal from the unstimulated controls was subtracted from values. Data shown is a representative example of n=3 independent experiments, mean +SD performed in triplicate.

[0104] Figure 2 shows a graph of the survival WT and CLEC12A-deficient (MICL- / -) mice infected with A. fumigatus (n=19 mice per group).

[0105] Figure 3 shows a graph of the survival times of mice infected with A. fumigatus and treated with mouse anti-CLEC12A antibodies (309) and those treated with isotype control antibodies (isotype).

[0106] Figure 4 shows a graph of the survival times of WT and CLEC12A-deficient

[0107] (MICL- / -) mice infected with Rhizopus delemar.

[0108] Figure 5 shows a graph of the survival of WT and CLEC12A-deficient (MICL- / -)

[0109] ) mice infected with Candida Albicans.

[0110] Examples

[0111] 1) Anti-CLEC12A antibodies:

[0112] The anti-CLEC12A antibodies of the present invention were produced using the methods described in Marshall et al. “Human MICL (CLEC12A) is differentially glycosylated and is down-regulated following cellular activation” European Journal of

[0113] Immunology. 2006 Aug;36(8):2159-69. doi: 10.1002 / eji.200535628.

[0114] Three anti-CLEC12A antibody variants were produced: (i) comprising HCVR encoded by nucleic acid sequence of SEQ ID NO: 19 and LCVR encoded by nucleic acid sequence of SEQ ID NO: 20 (named “BC2”), (ii) comprising HCVR encoded by nucleic acid sequence of SEQ ID NO: 21 and LCVR encoded by nucleic acid sequence of SEQ ID NO: 22 (named “EE8”); and (iii) comprising HCVR encoded by nucleic acid sequence of SEQ ID NO: 23 and LCVR encoded by nucleic acid sequence of SEQ ID NO: 24 (named “HB3”).

[0115] The anti-CLEC12A antibody variants comprised the following CDRs: (i) HCVR comprising CDR1 encoded by nucleic acid sequence of SEQ ID NO: 1, CDR2 encoded by nucleic acid sequence of SEQ ID NO: 2, CDR3 encoded by nucleic acid sequence of SEQ ID NO: 3 and a LCVR comprising CDR1 encoded by nuclei acid sequence of SEQ ID NO: 4, CDR2 encoded by nucleic acid sequence of SEQ ID NO: 5, CDR3 encoded by nucleic acid sequence of SEQ ID NO: 6 (BC2), (ii) HCVR comprising CDR1 encoded by nucleic acid sequence of SEQ ID NO: 7, CDR2 encoded by nucleic acid sequence of SEQ ID NO: 8, CDR3 encoded by nucleic acid sequence of SEQ ID NO: 9 and a LCVR comprising CDR1 encoded by nuclei acid sequence of SEQ ID NO: 10, CDR2 encoded by nucleic acid sequence of SEQ ID NO: 11, CDR3 encoded by nucleic acid sequence of SEQ ID NO: 12 (EE8), (iii) HCVR comprising CDR1 encoded by nucleic acid sequence of SEQ ID NO: 13, CDR2 encoded by nucleic acid sequence of SEQ ID NO: 14, CDR3 encoded by nucleic acid sequence of SEQ ID NO: 15 and a LCVR comprising CDR1 encoded by nuclei acid sequence of SEQ ID NO: 16, CDR2 encoded by nucleic acid sequence of SEQ ID NO: 17, CDR3 encoded by nucleic acid sequence of SEQ ID NO: 18 (HB3).

[0116] 2) Aspergillus fumigatus systemic infection model:

[0117] Neutrophils play a crucial role in protection against fungal pathogens, such as A. fumigatus. Protective neutrophil responses to A. fumigatus hyphae involve ROS production and NET formation.

[0118] Figure 1 shows that both CLEC12A-deficient mouse neutrophils and human neutrophils treated with anti-CLEC12A antibodies of the present invention induce higher levels of NET formation in vitro in response to this pathogen. NET formation is critical in the immune response to A. fumigatus, restraining fungal growth and preventing tissue dissemination. Figure 1 shows the use of the HB3 antibodies, however, similar results were also achieved for the EE8 and BC2 antibodies.

[0119] The survival of MICL / _(MICL-deficient or CLEC12A-deficient) mice following infection with A. fumigatus was investigated to demonstrate the role of CLEC12A receptor in A. fumigatus infection.

[0120] 6-8 week-old MICL / _(MICL-deficient or CLEC12A-deficient) and C57BL / 6J (WT) mice were injected intravenously with 106A. fumigatus ATCC 13073 conidia, as described in Stappers, M. H. T. et al., Nature, 555, 382-386 (2018).

[0121] Figure 2 shows that MICL / _(MICL-deficient or CLEC12A-deficient) mice are significantly more protected against A. fumigatus than WT mice. The anti-CLEC12A antibodies of the present invention recapitulate the effects of MICL-deficient or CLEC12A-deficient (knockout) mice as the anti-CLEC12A antibodies act to block the function of the CLEC12A receptor. Thus, this experiment indicates the suitability of the anti-CLEC12A antibodies of the present invention in the treatment of infection with A. fumigatus.

[0122] Anti-CLEC12A antibodies provide protection against Aspergillus fumigatus infection in immune suppressed mice:

[0123] Mice were immunosuppressed using triamcinolone. Mice were inoculated intranasally at day zero (DO) with 5xl04spores conidia of Aspergillus fumigatus ATCC 13073 in 40 pL. When first mouse started to show clinical symptoms (day 2 in both experiments) they were treated with mouse anti-CLEC12A antibodies (309) or isotype control antibodies (i.e. antibodies that do not recognise the antigen) at 0.3mg / ml / day for 3 consecutive days.

[0124] Figure 3 shows that the anti-CLEC12A antibodies provide significant protection against Aspergillus fumigatus infection in immune supressed mice. This directly relates to human susceptibility to the infection.

[0125] 3) Mucormycosis and vulvovaginal candidiasis infection models

[0126] The survival of MICL / _(MICL-deficient or CLEC12A-deficient mice following infection with Rhizopus delemar was investigated to demonstrate the role of CLEC12A in mucormycosis.

[0127] WT and MICL / _(MICL-deficient or CLEC12A-deficient) mice were injected intravenously with IxlO5swollen spores of Rhizopus delemar RA 99-880 in 100 pL.

[0128] Figure 4 shows that MICL / _(MICL-deficient or CLEC12A-deficient) mice are protected against mucormycosis infection. The survival of MICL- / -(MICL-deficient or CLEC12A-deficient mice) following infection with Candida Albicans (C. Albicans) to demonstrate the role of CLEC12A in vulvovaginal candidiasis (VVC) infection.

[0129] Prior to vaginal injection of C. Albicans (day -3) induction of a pseudoestrus condition in mice (WT and MICL- / -) with a subcutaneous injecting of oestradiol valerate

[0130] (in sesame oil) is carried out to mimic human vagina. After 3 days, an intravaginal inoculation of C. Albicans.

[0131] Figure 5 shows that MICL- / -(MICL-deficient or CLEC12A-deficient) mice are protected against vulvovaginal candidiasis infection. The above examples demonstrate the suitability of the use of the anti-CLEC12A antibodies of the present invention in the treatment of a variety of fungal infections.

[0132] The above embodiments are described by way of example only. Many variations are possible without departing from the scope of the invention.

[0133] SEQUENCE LISTINGS

[0134] SEQ ID NO: 1 (BC2_MiCL_Heavy CDR1 )

[0135] GGCTACACTTTCACCAGCTACTGG SEQ ID NO: 2 (BC2_MiCL_Heavy CDR2 )

[0136] ATAATTCATCCTAATAGTGGTAGTACTAACTACAATGAGAAGT

[0137] SEQ ID NO: 3 (BC2_MiCL_Heavy CDR3)

[0138] GCACGTTACTACGGTACTAGCACAAGGGACTTTGACTACT

[0139] SEQ ID NO: 4 (BC2_MiCL_Kappa CDR1 )

[0140] AGTGCCAGCTCAAGTGTAAGTTACATGCAC

[0141] SEQ ID NO: 5 (BC2_MiCL_Kappa CDR2) GACACATCCAAACTGGCTTCT

[0142] SEQ ID NO: 6 (BC2_MiCL_Kappa CDR3)

[0143] CAACAGTGGAGTAGTAACCCACCGACG SEQ ID NO: 7 (EE8_Heavy CDR1 )

[0144] GGCTACACTTTCACCAGCTACTGG

[0145] SEQ ID NO: 8 (EE8_Heavy CDR2 ) ATGATTCATCCTAATAGTGGAAGTACTAAGTACAATGAGAAGT

[0146] SEQ ID NO: 9 (EE8_Heavy CDR3)

[0147] GCACGTTACTACGGTAGTAGCACATGGGACTTTGACTACT SEQ ID NO: 10 (EE8_Kappa CDR1 )

[0148] AGTGCCAGCTCAAGTGTACGTTACATGCAC

[0149] SEQ ID NO: 11 (EE8_Kappa CDR2)

[0150] GACACATCCAAACTGGCTTCT

[0151] SEQ ID NO: 12 (EE8_Kappa CDR3)

[0152] CAGCAGTGGAGTAGTAACCCACCGACG

[0153] SEQ ID NO: 13 (HB3_Heavy CDR1 ) GGCTATACTTTCACCAGCTACTGG

[0154] SEQ ID NO: 14 (HB3_Heavy CDR2)

[0155] ATGATTCATCCTAATAGTGGTAGTAGTCACTATAATGAGAACT

[0156] SEQ ID NO: 15 (HB3_Heavy CDR3)

[0157] GCACGTTACTACGGTACTAGTTCAAGGGACTTTGACTTCT

[0158] SEQ ID NO: 16 (HB3_Kappa CDR1 ) AGTGCCAGTTCAAGTGTAAGGTACATGCAC

[0159] SEQ ID NO: 17 (HB3_Kappa CDR2)

[0160] GACACATCCAAACTGGCTTCT SEQ ID NO: 18 (HB3_Kappa CDR3 )

[0161] CAGCAGTGGAGTAGTAACCCACCGACG

[0162] SEQ ID NO: 19 (BC2_MiCL_Heavy) ATGGGATGGAGCTATATCATCCTCTTTTTGGTAGCAACAGCTACAGG

[0163] TGTCCACTCCCAGGTCCAACTGCAGCAGCCTGGGGCTGAGCTGGTA

[0164] AAGCCTGGGGCTTCAGTGAAGTTGTCCTGCAAGGCTTCTGGCTACAC

[0165] TTTCACCAGCTACTGGATGCACTGGGTGAAGCAGAGGCCTGGACAA

[0166] GGCCTTGAGTGGATTGGAATAATTCATCCTAATAGTGGTAGTACTAA

[0167] CTACAATGAGAAGTTCAAGACCAAGGCCACACTGACTGTAGACAAA

[0168] TCCTCCAGCACAGCCTACATGCAACTCAGCAGCCTGACATCTGAGG

[0169] ACTCTGCGGTCTATTACTGTGCACGTTACTACGGTACTAGCACAAGG

[0170] GACTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCAGC C

[0171] SEQ ID NO: 20 (BC2_MiCL_Kappa)

[0172] ATGGATTTTCAAGTGCAGATTTTCAGCTTCCTGCTAATCAGTGCCTC

[0173] AGTCATAATATCCAGAGGACAAATTGTTCTCACCCAGTCTCCAGCA

[0174] ATCATGTCTGCATTTCCAGGGGAGAAGGTCACCATGACCTGCAGTG

[0175] CCAGCTCAAGTGTAAGTTACATGCACTGGTACCAGCAGAAGTCAGG

[0176] CACCTCCCCCAAAAGATGGATTTATGACACATCCAAACTGGCTTCTG

[0177] GAGTCCCTGCTCGCTTCAGTGGCAGCGGGTCTGGGACCTCTTACTCT

[0178] CTCACAATCAGCAGCATGGAGGCTGAAGATGCTGCCACTTATTACT

[0179] GCCAACAGTGGAGTAGTAACCCACCGACGTTCGGTGGAGGCACCAA

[0180] GCTGGAAATCAAACGGGCTGATGCTGCACCAACTGTATCCATCTTCC

[0181] CA SEQ ID NO: 21 (EE8_Heavy)

[0182] ATGGGATGGAGCTATATCATCCTCTTTTTGGTAGCAACAGCTGCAGG

[0183] TGTCCACTCCCAGGTCCAACTGCAGCAGCCTGGGGCTGAGCTGGTT

[0184] AAGCCTGGGGCTTCAGTGAAGTTGTCCTGCAAGGCTTCTGGCTACAC

[0185] TTTCACCAGCTACTGGATGCACTGGGTGAAGCAGAGGCCTGGACAA

[0186] GGCCTTGAGTGGATTGGAATGATTCATCCTAATAGTGGAAGTACTA

[0187] AGTACAATGAGAAGTTCACGAACAAGGCCACACTGACTGTAGACAA

[0188] ATCCTCCAGCACAGCCTACATGCAACTCAGCAGCCTGACATCTGAG

[0189] GACTCTGCGGTCTATTACTGTGCACGTTACTACGGTAGTAGCACATG

[0190] GGACTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCAG

[0191] CCAAAACAACACCCCCATCAGTCTATCCACTGGCCCCTGGGTGT

[0192] SEQ ID NO: 22 (EE8_Kappa)

[0193] ATGGATTTTCAAGTGCAGATTTTCAGCTTCCTGCTAATCAGTGCCTC

[0194] AGTCAAAATATCCAGAGGACAAATTGTTCTCACCCAGTCTCCAGCA

[0195] ATCATGTCTGTATTTCCAGGGGAGAAGGTCACCATGACCTGCAGTG

[0196] CCAGCTCAAGTGTACGTTACATGCACTGGTACCAGCAGAAGTCAGG

[0197] CACCTCCCCCAAAATATGGATTTATGACACATCCAAACTGGCTTCTG

[0198] GAGTCCCTGGTCGCTTCAGTGGCAGTGGGTCTGGGACCTCTTACTCT

[0199] CTCACAATCAGCAGCGTGGGGGCTGAAGATGCTGCCACTTATTTCTG

[0200] CCAGCAGTGGAGTAGTAACCCACCGACGTTCGGTGGAGGCACCAAG CTGGAAATCAAACGGGCTGATGCTGCACCAACTGTATCCATCTTCCC

[0201] ACCATCCAGTGAGCAGTTAACATCTGGAGGTGCCTCAGTCGTGTGCT

[0202] TCTTGAACAACTTCTACCCCAAAGACATCAATGTATTCTTGCTA

[0203] SEQ ID NO: 23 (HB3_Heavy)

[0204] ATGGGATGGAACTATATCATCCTCTTTTTGGTAGCAACAGCTACAGG

[0205] TGTCCACTCCCAGGTCCAACTGCAGCAGCCTGGGGCTGAGCTGGTA

[0206] AAGCCTGGGGCTTCAGTGAAGTTGTCCTGCAAGACTTCTGGCTATAC

[0207] TTTCACCAGCTACTGGATGCACTGGGTGAAGCAGCGGCCTGGACAT

[0208] GGCCTTGAGTGGATTGGAATGATTCATCCTAATAGTGGTAGTAGTCA

[0209] CTATAATGAGAACTTCGAGAACAAGGCCACACTGACTGTAGACAAA

[0210] TCCTCCAGCACAGCCTACATGCAACTCAGCAGCCTGACATCTGAGG

[0211] ACTCTGCGGTCTATTACTGTGCACGTTACTACGGTACTAGTTCAAGG

[0212] GACTTTGACTTCTGGGGCCAAGGCACCACTCTCACAGTCTCCTCAGC

[0213] CAAAACGACACCCCCATCTGTCTATCCACTGGCCCCTGGATCTGCTG

[0214] CCCAAACTAACTCCATGGTGACCCTGGGATGCCTGGTCAAGGGCTA

[0215] TTTCC

[0216] SEQ ID NO: 24 (HB3_Kappa)

[0217] ATGGATTTTCAAGTGCAGATTTTCAGCTTCCTGCTAATCAGTGCCTC

[0218] AGTCATAATATCCAGAGGACAAATTGTTCTCACCCAGTCTCCAGCA

[0219] ATCATGTCTGCATCTCCAGGGGAGAAGGTCACCATGACCTGCAGTG CCAGTTCAAGTGTAAGGTACATGCACTGGTACCAGCAGAAGTCAGG

[0220] CACCTCCCCCAAAAGATGGCTTTATGACACATCCAAACTGGCTTCTG

[0221] GAGTCCCTGCTCGCTTCAGTGGCAGCGGGTCTGGGACCTCTTACTCT

[0222] CTCTCAATCAGCAGCATGGAGGCTGAAGATGCTGCCACTTATTACTG

[0223] CCAGCAGTGGAGTAGTAACCCACCGACGTTCGGTGGAGGCACCAAG

[0224] CTGGAAATCAAACGGGCTGATGCTGCACCAACTGTATCCATCTTCCC

[0225] ACCATCCAGTGAGCAGTTAACATCTGGAGGTGCCTCAGTCGTGTG

[0226] SEQ ID NO: 25 (BC2_MiCL_Heavy)

[0227] MGWSYIILFLVATATGVHSQVQLQQPGAELVKPGASVKLSCKASGYTF

[0228] TSYWMHWVKQRPGQGLEWIGIIHPNSGSTNYNEKFKTKATLTVDKSSS

[0229] TAYMQLSSLTSEDSAVYYCARYYGTSTRDFDYWGQGTTLTVSSA

[0230] SEQ ID NO: 26 (BC2_MiCL_Kappa)

[0231] MDFQVQIFSFLLISASVIISRGQIVLTQSPAIMSAFPGEKVTMTCSASSSV

[0232] SYMHWYQQKSGTSPKRWIYDTSKLASGVPARFSGSGSGTSYSLTISSM

[0233] EAEDAATYYCQQWSSNPPTFGGGTKLEIKRADAAPTVSIFP

[0234] SEQ ID NO: 27 (EE8_Heavy)

[0235] MGWSYIILFLVATAAGVHSQVQLQQPGAELVKPGASVKLSCKASGYTF

[0236] TSYWMHWVKQRPGQGLEWIGMIHPNSGSTKYNEKFTNKATLTVDKSS STAYMQLSSLTSEDSAVYYCARYYGSSTWDFDYWGQGTTLTVSSAKT

[0237] TPPSVYPLAPGC

[0238] SEQ ID NO: 28 (EE8_Kappa)

[0239] MDFQVQIFSFLLISASVKISRGQIVLTQSPAIMSVFPGEKVTMTCSASSSV

[0240] RYMHWYQQKSGTSPKIWIYDTSKLASGVPGRFSGSGSGTSYSLTISSVG

[0241] AEDAATYFCQQWSSNPPTFGGGTKLEIKRADAAPTVSIFPPSSEQLTSG

[0242] GASVVCFLNNFYPKDINVFLL

[0243] SEQ ID NO: 29 (HB3_Heavy)

[0244] MGWNYIILFLVATATGVHSQVQLQQPGAELVKPGASVKLSCKTSGYTF

[0245] TSYWMHWVKQRPGHGLEWIGMIHPNSGSSHYNENFENKATLTVDKSS

[0246] STAYMQLSSLTSEDSAVYYCARYYGTSSRDFDFWGQGTTLTVSSAKTT

[0247] PPSVYPLAPGSAAQTNSMVTLGCLVKGYF

[0248] SEQ ID NO: 30 (HB3_Kappa)

[0249] MDFQVQIFSFLLISASVIISRGQIVLTQSPAIMSASPGEKVTMTCSASSSV

[0250] RYMHWYQQKSGTSPKRWLYDTSKLASGVPARFSGSGSGTSYSLSISSM

[0251] EAEDAATYYCQQWSSNPPTFGGGTKLEIKRADAAPTVSIFPPSSEQLTS

[0252] GGASVV

Claims

CLAIMS1. An anti-CLEC12A antibody or antigen-binding fragment thereof for use in the treatment of a microbial infection.

2. An anti-CLEC12A antibody or antigen-binding fragment thereof, comprising one of the following:(i) a heavy chain variable region comprising a CDR1 encoded by a nucleic acid sequence of SEQ ID NO: 1, a CDR2 encoded by a nucleic acid sequence of SEQ ID NO: 2, and a CDR3 encoded by a nucleic acid sequence of SEQ ID NO: 3; and a light chain variable region comprising a CDR1 encoded by a nucleic acid sequence of SEQ ID NO: 4, a CDR2 encoded by a nucleic acid sequence of SEQ ID NO: 5, and a CDR3 encoded by a nucleic acid sequence of SEQ ID NO: 6;(ii) a heavy chain variable region comprising a CDR1 encoded by a nucleic acid sequence of SEQ ID NO: 7, a CDR2 encoded by a nucleic acid sequence of SEQ ID NO: 8, and a CDR3 encoded by a nucleic acid sequence of SEQ ID NO: 9; and a light chain variable region comprising a CDR1 encoded by a nucleic acid sequence of SEQ ID NO: 10, a CDR2 encoded by a nucleic acid sequence of SEQ ID NO: 11, and a CDR3 encoded by a nucleic acid sequence of SEQ ID NO: 12;(iii) a heavy chain variable region comprising a CDR1 encoded by a nucleic acid sequence of SEQ ID NO: 13, a CDR2 encoded by a nucleic acidsequence of SEQ ID NO: 14, and a CDR3 encoded by a nucleic acid sequence of SEQ ID NO: 15; and a light chain variable region comprising a CDR1 encoded by a nucleic acid sequence of SEQ ID NO: 16, a CDR2 encoded by a nucleic acid sequence of SEQ ID NO: 17, and a CDR3 encoded by a nucleic acid sequence of SEQ ID NO: 18.

3. The anti-CLEC12A antibody or antigen-binding fragment thereof as claimed in claim 2, wherein the anti-CLEC12A antibody or antigen-binding fragment thereof comprises one of the following:(i) a heavy chain variable region comprising an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 25 and a light chain variable region comprising an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 26;(ii) a heavy chain variable region comprising an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 27 and a light chain variable region comprising an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 28;(iii) a heavy chain variable region comprising an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 29 and a light chain variable region comprising an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 30.

4. A nucleic acid sequence encoding the anti-CLEC12A antibody or antigen-binding fragment as claimed in claim 2 or 3.

5. The nucleic acid sequence as claimed in claim 4, comprising a nucleic acid sequence with at least 80% sequence identity to SEQ ID NO: 19 encoding the heavy chain variable region of the antibody or antigen-binding fragment thereof, and a nucleic acid sequence with at least 80% sequence identity to SEQ ID NO: 20 encoding the light chain variable region of the antibody or antigen-binding fragment thereof.

6. The nucleic acid sequence as claimed in claim 4, comprising a nucleic acid sequence with at least 80% sequence identity to SEQ ID NO: 21 encoding the heavy chain variable region of the antibody or antigen-binding fragment thereof, and a nucleic acid sequence with at least 80% sequence identity to SEQ ID NO: 22 encoding the light chain variable region of the antibody or antigen-binding fragment thereof.

7. The nucleic acid sequence as claimed in claim 4, comprising a nucleic acid sequence with at least 80% sequence identity to SEQ ID NO: 23 encoding the heavy chain variable region of the antibody or antigen-binding fragment thereof, and a nucleic acid sequence with at least 80% sequence identity to SEQ ID NO: 24 encoding the light chain variable region of the antibody or antigen-binding fragment thereof.

8. The anti-CLEC12A antibody or antigen-binding fragment thereof as claimed in any one of claims 1 to 3, wherein the antibody or antigen-binding fragment thereof is a human, chimeric, humanized or deimmunized antibody or antigen-binding fragment thereof.

9. The anti-CLEC12A antibody or antigen-binding fragment thereof as claimed in any one of claims 1 to 3 or 8, wherein the antibody or antigen-binding fragment thereof is a monoclonal antibody or fragment thereof.

10. The anti-CLEC12A antibody or antigen-binding fragment thereof as claimed in any one of claims 2, 3 or 8 to 9 for use in the treatment of a microbial infection.

11. The anti-CLEC12A antibody or antigen-binding fragment thereof according to claim 1 or claim 10, wherein the microbial infection is a fungal infection.

12. A vector comprising the nucleic acid sequence of any one of claims 4-7.

13. A host cell comprising the vector as claimed in claim 12.

14. A pharmaceutical composition comprising the anti-CLEC12A antibody or antigen binding fragment thereof as claimed in any one of claims 2, 3 or 8 to 10, and one or more pharmaceutically acceptable diluents or excipients.

15. The pharmaceutical composition as claimed in claim 14, further comprising one or more additional therapeutic agents.

16. The pharmaceutical composition as claimed in claim 14 or 15 for use in the treatment of a microbial infection.

17. A method of treating an individual with a microbial infection, the method comprising administering to the individual a therapeutically effective amount of the anti-CLEC12A antibody or antigen-binding fragment as claimed in any one of claims 2, 3 or 8 to 10.

18. An anti-CLEC12A antibody or antigen-binding fragment thereof comprising one of the following:(i) a heavy chain variable region comprising at least one CDR encoded by a nucleic acid sequence selected from SEQ ID NO: 1, 2, and 3, and a light chain variable region comprising at least one CDR encoded by a nucleic acid sequence selected from SEQ ID NO: 4, 5 and 6; (ii) a heavy chain variable region comprising at least one CDR encoded by a nucleic acid sequence selected from SEQ ID NO: 7, 8, and 9, and a light chain variable region comprising at least one CDR encoded by a nucleic acid sequence selected from SEQ ID NO: 10, 11 and 12;(iii) a heavy chain variable region comprising at least one CDR encoded by a nucleic acid sequence selected from SEQ ID NO: 13, 14, and 15, and a light chain variable region comprising at least one CDR encoded by a nucleic acid sequence selected from SEQ ID NO: 16, 17 and 18.

Images